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Examples of therapeutics projects previously funded by Innovations. See other areas.

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Pathfinder Award Development of novel polysialyltransferase inhibitors for the treatment of neuroblastoma Neuroblastoma is the most common extra-cranial paediatric cancer, typically affecting children below 2 years of age. Up to 2,500 new cases are diagnosed in Europe and the USA combined each year. Despite recent advances in therapy, post-treatment relapse is common, meaning there is a desperate need for novel therapies, with 5-year survival for children diagnosed with high-risk disease currently less than 50%. The burden of drug-related toxicity experienced by these patients is such that the scope for further toxic chemotherapy is limited.

One strategy is to prevent disease progression by targeting processes that drive metastatic spread of the cancer. Dr Robert Falconer and colleagues at the Institute of Cancer Therapeutics, University of Bradford are developing a completely novel approach to therapy, by targeting polysialyltransferase (polyST), an enzyme which plays a key role in neuroblastoma dissemination. PolyST is responsible for the synthesis of polysialic acid, which is exclusively expressed on neuroendocrine tumours, providing an opportunity for a non-toxic, selective therapy for neuroblastoma.  
This Pathfinder project will focus on validation of a series of hit polyST inhibitors using biophysical techniques, and to use this information to identify new inhibitors using computational chemistry and in vitro pharmacological assays. Beyond this Pathfinder award, this work will pave the way to lead identification and demonstration of pre-clinical proof-of-concept.
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Pathfinder Award A new biomaterial platform for integrated cell therapy research, manufacturing and clinical administration The development of cell therapeutics, and their clinical administration, is staged in an inefficient, compartmentalised manner. There are major disconnects along the development pathway (from the research phase right through to clinical administration), with cellular performance expected to be replicable across 2D and suspension formats and also within complex biological environments. Furthermore, there are specific additional barriers to commercial uptake, which include high cost, poorly-scalable manufacturing, reliance on damaging proteolytic enzymes for cell harvesting and poor cell retention and survival post-implantation.

Dr Robin Quirk and the team at Locate Therapeutics propose to address these challenges by exemplifying their Reversible Porous Matrix (RPMax) platform as an embedded constant across the entire cell therapy value chain. RPMax is a new, thermoreversibly-setting particle-based matrix for tissue repair, offering opportunities for stem cell research, fully-automatable 3D cell manufacturing and clinical administration. This project aims to tailor the platform to key clinical cell types, to demonstrate performance benefits over current approaches and  generate preclinical proof-of-concept data.
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Pathfinder Award A novel gene therapy construct providing neuro-protection against glaucoma Glaucoma is the second leading cause of blindness worldwide. The NHS estimates that there are more than 500,000 people diagnosed with glaucoma, with many more unaware that they have the condition. In 2010, it was estimated that 8.4 million people worldwide were blind from primary open-angle glaucoma which is predicted to rise to over 11 million by 2020. Elevated ocular pressure is associated with glaucoma and is the focus of current treatments. 

However, high pressure is only a risk factor, and not the sole cause of the disease, with 10% of glaucoma sufferers having normal pressure. This, combined with poor treatment compliance leads to the blindness of glaucoma sufferers.  While the cause of glaucoma is multi-factorial, the disease ultimately leads to death of retinal ganglion cells, which causes blindness. Dr Peter Widdowson and the team at Quethera are utilising recombinant adeno-associated viral vector-based gene therapy to deliver neuro-protectants, shielding retinal ganglion cells, preserving them from death, and ultimately delaying blindness associated with the disease following a single injection to the eye. The Pathfinder Award will allow individual components of the gene therapy to be examined in vivo and ensure that they are functioning at optimal levels before they are assembled into the final gene therapy construct.
Seeding Drug Discovery Developing drugs to treat myotonic dystrophy Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults.  It is a highly debilitating condition with an average life expectancy of 58 years, affecting more than 100,000 patients in developed countries.  DM1 is primarily a neuromuscular disorder, which also affects a range of other systems including the heart, brain, endocrine and digestive systems.  Patients may also show psychological dysfunction, cognitive impairment and excessive daytime sleepiness.  There is no treatment for DM1 and all features show an obvious deterioration with time.

DM1 is caused by a repeat expansion mutation in the 3’ untranslated region of the DMPK gene.  Unaffected people have 5 to 30 copies of a CTG sequence whereas patients may have hundreds or sometimes thousands of copies.  When expressed the DMPK expansion transcripts remain in the nucleus where they form distinct spots or foci.  Professors Chris Hayes and David Brook at the University of Nottingham developed an assay to screen for compounds that might provide a treatment for DM1.  They identified small molecules that target a novel protein and destroy the spots in DM1 cells, thereby leading to a significant reduction in the faulty RNA and other molecular features of the disorder.  This Seeding Drug Discovery award, in collaboration with Argenta Discovery, is based on targeting this novel protein, by generating unique molecules that are selective and more suitable for oral administration to patients.  Professors Hayes and Brook anticipate that a successful drug would target most/all features of the disease.
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Pathfinder Award Identification of small molecule Onchocerca macrofilaricidal leads for the treatment of river blindness Professor Fidelis Cho-Ngwa at the University of Buea, Cameroon, in collaboration with industry partner Merck, will use this Pathfinder Award to initiate a drug discovery project to develop a cure for onchocerciasis.  Onchocerciasis, also known as river blindness is a neglected tropical disease, afflicting some 37 million people in poor tropical countries. Despite being the second leading infectious cause of blindness globally, and a significant contributor to low life expectancy in the endemic countries, there is yet to be a cure (a macrofilaricide) for the disease. A macrofilaricide, especially one that does not kill Loa loa, to avoid serious adverse events, is a critical unmet need. Being a neglected disease, a not-for-profit strategy, based on global donations and philanthropy would be required to develop the drug.

Merck has 2.5 million diverse small molecules in its portfolio. In response to a WIPO Re:Search request, Merck will donate highly potent molecules, most of them HSP90 inhibitors for testing in well-established phenotypic assays and jird model at the pan-African ANDI Centre of Excellence for Onchocerciasis Drug Research, University of Buea, Cameroon. Inhibition of HSP90, a target present in Onchocerca, has previously been shown to be potent against filariae. At the end of the Pathfinder project, the team hope to deliver a handful of macrofilaricidal leads to support global efforts for the development of an onchocerciasis cure, that can be used in control programmes to eliminate the disease, and also safely used in areas where L. loa is also prevalent.
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Pathfinder Award Development of small molecule inhibitors of Ebola virus genome replication This Pathfinder project will address infection with Ebola virus (EBOV), which has a human mortality rate of over 50%.  EBOV is a member of the Filoviridae family (genus Ebolavirus), a negative strand RNA virus that is highly transmissible and causes severe haemorrhagic fever. The recent outbreak of EBOV in West Africa has highlighted the lack of effective therapeutic options for the treatment of this infection. Efficacious small molecule inhibitors of the virus are therefore needed for the rapid treatment of EBOV infected individuals, but their development has been hampered by the requirement to propagate EBOV under Biological Safety Level 4 (BSL4) containment.

The project team, led by Professor Mark Harris at University of Leeds, propose to use a combination of in silico drug design and a mini-genome system, which accurately and faithfully recapitulates the essential processes of EBOV gene transcription and genome replication under BSL2 conditions. The team will design small molecule inhibitors based on known high-resolution structures of EBOV proteins involved in these processes, in particular focussing on the essential nucleocapsid protein.  This approach builds on existing strengths at the University of Leeds, combining an innovative approach to in silico drug design with extensive experience in both virology and structural biology. The project aims to deliver drug-like lead compounds that can be further developed into therapeutic agents.
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Pathfinder Award New therapeutic avenues in Sjogren’s syndrome: exploring the role of PEPITEM in an orphan disease Sjogren’s syndrome is the second most diffuse rheumatic autoimmune disease in the UK. Current treatment includes eye drops and saliva substitutes. In some cases patients are treated with immunosuppressive drugs but with scarce benefit. There is no disease-modifying therapy for this disease and it is not a priority area of research for the pharmaceutical industry. It is known that Sjogren’s syndrome is driven by the recruitment of immune cells into the salivary glands. The subsequent production of autoreactive antibodies destroy the salivary tissue and drive systemic manifestations such as arthritis and fatigue.

To enter the salivary glands, immune cells first need to cross the blood vessel wall. Importantly, Dr Francesca Barone and colleagues at the University of Birmingham have identified a novel molecule called PEPITEM that stops the recruitment of immune cells.  With Pathfinder funding, Dr Barone and her team aim to determine whether PEPITEM levels can predict who will develop Sjogren’s syndrome and whether therapeutic administration of PEPITEM prevents salivary gland inflammation in models of the disease.  By better understanding the biology of PEPITEM, it may be possible to address both diagnostic and therapeutic  needs for these patients.
Seeding Drug Discovery Development of novel antagonists of the cell surface adrenomedullin 2 receptor for the treatment of pancreatic cancer Pancreatic cancer is the 10th most common cancer, but in the next 15 years, it will become the second highest cause of cancer-related death.  Unlike almost all other cancers, the prognosis has not changed in the last 30 years.  After diagnosis, outcomes are very poor, with 1-year and 5-year survival rates of <25% and <5% respectively.  The best current therapies offer only a few months of increased life expectancy, and patients’ quality of life is poor despite palliative treatments.

There is clearly a pressing need for better treatments for pancreatic cancer.  A team from the University of Sheffield led by Professor Tim Skerry, with Peakdale Molecular and Sandexis Medicinal Chemistry have been awarded Seeding Drug Discovery funding to develop selective antagonists of the adrenomedullin-2 receptor.  Adrenomedullin is a hormone involved in cancer growth and spread, which also has important roles in the control of blood pressure. Adrenomedullin acts through two different receptors one of which mostly regulates blood pressure.  The other has important roles in cancer biology. The team have shown that in model systems, blockade of the receptor reduces tumour growth and spread. They will develop their existing novel lead compounds to block the adrenomedullin-2 receptor and inhibit its important roles in cancer, while keeping its normal functions
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Pathfinder Award Enabling phenotypic screening to discover treatments for cryptosporidiosis The protozoan parasite Cryptosporidium causes acute enteritis with severe diarrhea as lead symptom. Recent large-scale epidemiological analysis of the causes of life-threating diarrhea in small children around the world has identified Cryptosporidium as the second most important diarrheal pathogen after rotavirus.  Importantly, in those patients in gravest danger, malnourished children and immuno-compromised patients, nitazoxanide shows no benefit over placebo. Drug screening so far has been limited, and the overall research and development infrastructure for this important pathogen is underpowered, in part this is the consequence of lack of suitable experimental tools.

This Pathfinder Award project will synergize the University of Georgia Research Institute’s (UGA) expertise in parasite molecular genetics with the Novartis Institute for Tropical Diseases (NITD) expertise on phenotypic screening and drug discovery. Taking advantage of the UGA team’s recent breakthrough with transgenesis, they will develop luciferase based screening assays in tissue culture and animal models and benchmark them against staining-based assays.  Transgenic assays are likely to have multiple advantages including higher sensitivity, homogenous read-out and exquisite specificity and they will enhance throughput in vitro and in vivo. The team will use these technologies to run a pilot phenotypic screen with a set of chemically diverse anti-parasitic compounds.  The deliverables of the project are validating a reporter based phenotypic assay that will enable comprehensive cryptosporidiosis drug discovery.  The project will expect to identify a set of in vitro and in vivo active compounds that will be used to explore target-deconvolution. 
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Pathfinder Award Novel wall teichoic acid inhibitor for treatment of bacterial infections Effective treatment of bacterial infections is an essential component of modern medicine. To that end, antibiotics have played a central role in saving millions of lives. Antibiotic resistance – when bacteria change so that antibiotics no longer work - is growing at a dangerously high rate and poses one of the greatest public health threats of our time. Antibiotic resistance would threaten routine surgery as infections become untreatable. Some types of treatment such as cancer chemotherapy and organ transplantation, which suppresses the patient’s immune system, would no longer be viable.

There is a need for the development of new antibacterial compounds especially with novel modes of action. Dr Ajay Mistry and the team at Oppilotech Ltd. have discovered a compound (OPT-1) that has potent antibacterial properties and is modulating a novel pathway in bacteria that is not targeted by any of the approved antibiotics. In vitro data has also been generated that indicates that OPT-1, in some isolates of MRSA, reverses their resistance to β-lactams, making them sensitive to antibiotics to which they were once resistant. This “potentiating” observation could have an enormous positive impact to the antibiotic landscape by making once obsolete antibiotics useful again. The project is aimed at further characterising the antibacterial and re-sensitising activities of OPT-1.
Pathfinder Award Identification of novel compounds for the treatment of pulmonary hypertension Pulmonary arterial hypertension is an incurable progressive condition and has a devastating impact on the ability to lead a normal life.  The condition causes constriction of pulmonary arteries, characterized by high blood pressure in arteries of the lungs, ultimately leading to right ventricular heart failure and death.  In patients with  heart failure,  injection of the peptide apelin  produces a  beneficial vasodilation of the peripheral vessels and acts as a very potent positive inotrope to increase cardiac output by acting at a single G-protein coupled receptor. The peptide is down-regulated in pulmonary arterial hypertension and it is proposed that an apelin agonist is required to replace the missing endogenous peptide. 

A limitation in the use of agonist drugs that mimic the action of endogenous chemical messenger, is that in addition to activating G-proteins to cause the desired therapeutic effect, signalling can involve coupling to β-arrestin, leading to unwanted internalization and desensitization, silencing the target receptor. A  collaboration between Dr Anthony Davenport, Dr Janet Maguire Professor Robert Glen from University of Cambridge has led to the discovery of the first ‘biased’ peptide agonist at the apelin receptor, that preferentially stimulate G-protein pathways over β-arrestin recruitment, with reduced internalization and desensitization. The first-in-human, proof of principle studies  show the ‘biased’ agonist improved vasodilatation and inotropic actions without receptor desensitization. The apelin receptor is one of the first G-protein coupled receptors pathways tractable to the design of biased agonists with proof-of-concept for utility in the clinic. The aim of this award in collaboration with the University of Dundee Drug Discovery Unit is to identify small molecule biased  apelin receptor agonists with drug like properties.
Translation Award Development of a novel small molecule based therapy for schizophrenia Schizophrenia is a severe and chronic mental health disorder that affects more than 21 million people worldwide. The disease is characterized by profound disruptions in thinking, affecting language, perception, and the sense of self, that typically includes psychotic episodes. Antipsychotics are the mainstay therapy for the treatment of schizophrenia. However, significant unmet need remains due to the limited efficacy and serious side effects associated with current antipsychotic medications.

Karuna Pharmaceuticals is developing KarXT, a novel product candidate for the treatment of schizophrenia that selectively targets the muscarinic system. KarXT is composed of xanomeline, a novel clinical-stage muscarinic receptor agonist and trospium chloride, an FDA-approved and well-established muscarinic receptor antagonist. Studies have shown that trospium does not enter the central nervous system and therefore the company expects that trospium would not inhibit xanomeline’s binding to muscarinic receptors in the brain.  Xanomeline has demonstrated efficacy in reducing psychosis and improving cognition in placebo-controlled human trials in both Alzheimer's disease and schizophrenia but has side effects associated with binding muscarinic receptors outside the central nervous system, limiting its therapeutic utility. Karuna believes that the addition of trospium chloride may reduce the side effects typically seen with xanomeline alone. Karuna plans to conduct a safety proof of concept study in 2016 to demonstrate that trospium chloride can improve xanomeline's tolerability profile, followed by a Phase II efficacy study.
Pathfinder Award Discovery and preclinical development of pan-serotype small molecule inhibitors against dengue virus NS5 RNA-dependent RNA polymerase (RdRp) using fragment screening Dengue is the most important mosquito-borne disease of humans and an important tropical infectious disease. The National Institute of Allergy and Infectious Diseases in the US lists the causative agent, dengue virus (DENV), which has four serotypes, as a 'category A' priority bio-threat pathogen. Approximately one third of the world’s population is at risk of infection, which occurs most frequently in children aged under 15. The spread of DENV in sub-tropical and tropical regions of the world has occurred over just a few decades due to globalisation and a failure to control the primary vector Aedes aegyptii. Ae. Albopictus, a secondary DENV vector, is spreading to cooler climates and so the disease is spreading further. A recent 2014 outbreak in Portugal underlines this concern. There are currently no marketed treatments for DENV infection, so there is a real need for an effective and safe treatment.

The ultimate aim of Effecta Pharma's dengue drug discovery programme is to identify pan-serotype inhibitors of the DENV NS5 polymerase protein for the treatment of dengue fever, and that bind to allosteric pockets of this critical viral protein, inhibiting viral replication and producing an antiviral effect. The Pathfinder Award will allow the development of the first step in this programme - the technology to target the NS5 conserved region and identify the first chemical starting points for drug discovery. Beyond the Pathfinder Award, these chemical starting points will be used for lead identification and optimisation, ultimately resulting in preclinical candidate drugs to be tested in a clinical PoC study.
Seeding Drug Discovery Development of hypoxia-activated DNA-PK inhibitors to enhance radiotherapy and improve outcomes for head and neck cancer Radiotherapy is used to treat 50% of all cancers and about half of these are cured. In head and neck cancers, typical treatment includes radiation that is targeted to the tumour in combination with high dose cisplatin that can have serious side effects. Radiotherapy results in the greatest response with cisplatin improving treatment success by ~10%.

It has been known for decades that one of the main reasons radiotherapy fails is due to the presence of radiation-resistant cells that have little oxygen (termed hypoxia) and many studies in patients have confirmed that hypoxia in tumours is correlated with poor treatment outcomes.  Dr Andrew Minchinton and colleagues, from the BC Cancer Agency in Canada, propose to develop a drug that prevents hypoxic cells from repairing radiation-induced damage to their DNA. The drug is only active in regions with no oxygen and only impacts those cells within the radiation beam; therefore, the drug is highly selective for its activity in hypoxic tumours and may reduce the need for additional chemotherapies that impact patient quality of life.  The net effect is that radiotherapy will have a stronger effect on the whole tumour as even the radiation-resistant hypoxic cells.
Translation Award Development of UCCB01-144 as a new treatment for stroke
Ischemic stroke, caused by a blood clot (thrombus or embolus), is a leading cause of death and disability worldwide with very few treatment options currently available.  The only approved treatment is thrombolysis by recombinant tissue plasminogen activator (rtPA) but less than 10% of patients receives this treatment due to time-restraints and contraindications.

Avilex pharma has developed UCCB01- 144, a neuro-protectant that has demonstrated great effect in preclinical studies of stroke. The Wellcome Trust and NovoSeeds have co-funded Avilex pharma to complete the preclinical development of UCCB01- 144 enabling future clinical studies that will hopefully lead to the approval of a novel treatment for stroke.
Seeding Drug Discovery Development of small molecule directly acting non-entry inhibitors against the human respiratory syncytial virus The aim of this project is to discover and develop potent and safe inhibitors of Respiratory Syncytial Virus (RSV) replication. Respiratory syncytial virus (RSV) is a virus that belongs, together with the measles, mumps and metapneumovirus to the family of Paramyxoviridae. This pathogen causes significant morbidity (bronchiolitis) and mortality in premature babies, in children under the age of one, in children with congenital heart and lung problems, in transplant patients and in immuno-compromised or elderly people.

Infection often requires prolonged hospitalisation, resulting in a high number of hospitalisation days during each epidemic season. Immunity against this virus is not long-lived and may allow re-infection every epidemic period. A vaccine is not available and prophylactic administration of humanised monoclonal antibodies is advised in high risk young infants. Access to potent RSV inhibitors for treating such infections is therefore highly needed. The teams of Prof. Johan Neyts of the Rega Institute, KU Leuven and of the Centre for Drug Design and Discovery (CD3) established by KU Leuven will collaborate to discover such new RSV inhibitors.
Seeding Drug Discovery Development of novel, boron-containing small molecules for the treatment of Chagas There is significant need for new treatments for Chagas disease. The disease is caused by the parasite Trypanosoma cruzi, and the disease can be spread by insect vectors, blood transfusions and from infected mothers to their newborn children. Between 10 and 20 million people, mostly in Central and South America are infected with the parasite and the disease results in over 10,000 annual deaths. Chagas disease kills more people in Latin America than any other parasitic disease, including malaria. Increasing numbers of cases are also being documented outside the normal high transmission areas, including in the U.S. and Europe.

Although in use for more than four decades, the two drugs available to treat Chagas--benznidazole and nifurtimox-- require a long course of therapy (60-90 days), have serious safety concerns (20-30% side effects result in treatment discontinuation), fail to cure in a significant number of patients (a result of natural resistance of some isolates to current drugs), and are contraindicated in pregnancy. Thus, there is a critical need for new drugs that address these significant shortcomings of existing therapeutics. Oxaboroles—pioneered by Anacor Pharmaceuticals--have emerged in preliminary studies as a class that can potentially fill this important need. The Wellcome Trust is funding a dedicated drug discovery effort at Anacor, partnered with the disease expertise in the laboratory of Professor Rick Tarleton of the University of Georgia. The objective of the project is to deliver a new drug candidate ready to enter clinical trials by 2016.
Pathfinder Award Accelerating developing world access to medicines Dr Mary Moran and colleagues at Policy Cures aim to identify scaleable new solutions that can improve access to innovative new medicines for the developing world. As developing country economies have grown, their interest in, and capacity to pay for, pharmaceuticals has increased; as have commercial initiatives aimed at accessing developing pharma markets.

This Pathfinder Award project aims to provide an up-to-date picture of the changing landscape of L&MIC access to commercial medicines, with a focus on identifying emerging market-based solutions and assessing their ability to provide sustainable, scaleable developing world access to commercial pharmaceuticals, including for the poor.
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Seeding Drug Discovery Inhibitors of protein arginine methyl transferase 5 (PRMT5) for the treatment of β-thalassemia and sickle cell disease Haemoglobin is the major protein in red blood cells essential for transport of oxygen from the lungs to tissues. The disorders of haemoglobin production are the commonest genetic diseases world-wide, affecting a staggering 10% of the global population. Two of these disorders, sickle cell disease (SCD) and β-thalassemia have devastating consequences for affected children, particularly in under-developed nations where effective therapies are unavailable.

In SCD, children experience numerous episodes of extreme pain due to damage of many organs and die before their teens. Death from untreated β-thalassemia occurs within the first three years of life. Even with optimal treatment, both these disorders are associated with a greater than thirty year reduction in life expectancy and significantly impaired quality of life.  The ill effects of these diseases are dramatically reduced in a minute percentage of adult patients who have naturally raised levels of the form of haemoglobin produced by the developing baby, fetal haemoglobin. Dr Ian Smith and colleagues at Cancer Therapeutics CRC Pty Ltd have identified a means to elevate fetal haemoglobin in all patients with SCD and β-thalassemia through a drug that targets a key factor responsible for the natural silencing of fetal gene expression at birth.  This Seeding Drug Discovery award aims to deliver a new targeted treatment for the haemoglobin disorders.
Seeding Drug Discovery Development of small molecule inhibitors of the Pseudomonas aeruginosa biofilms to treat chronic infections in cystic fibrosis patients Cystic fibrosis is the most common lethal, hereditary disease in Caucasian populations, affecting 1 in every 3,500 births in Europe with a current life expectancy of about 38 years. Most disease-related morbidity and mortality in CF is caused by progressive lung disease as a result of bacterial infection and airway inflammation, primarily associated with the effects of chronic Pseudomonas aeruginosa (PA) lung infection and the persistence of PA biofilms.

The Trust has awarded Antabio €4.0m over 2 years to fund the development of a small molecule inhibitor of PA biofilms to be used in combination with standard-of-care antibiotics. The objective of the project team, led by Principal Investigator Dr Martin Everett, Head of Biology at Antabio, is to identify a potent and selective lead series with efficacy in animals which will be capable of further development into a drug to augment the effectiveness of antibiotic therapy and result in enhanced suppression of the infection.
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Translation Award Development of a small molecule therapeutic for the orphan disease Creatine Transporter Deficiency  The Wellcome Trust has funded Lumos Pharma to conduct a preclinical and clinical development program to ensure safety and efficacy of its promising drug candidate for the treatment of Creatine Transporter Deficiency (CTD).  CTD is an inborn error of creatine metabolism and autism spectrum disorder. The primary clinical manifestations of the disease are moderate to severe intellectual disability, severe speech and language delay, seizures, and behaviors associated with autism. It is hoped that the drug candidate can allow the afflicted children to develop normally and lead normal lives.

 Lumos will conduct the nonclinical toxicology and safety pharmacology studies required to open an IND and initiate clinical studies. If these studies are successful Lumos will conduct a Phase I study in healthy volunteers to assess safety and tolerability and to further characterize the PK profile of the compound. Secondly, Lumos will conduct a Phase IIa study in CTD patients to examine efficacy.
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Translation Award Chemokine-based microbicides: Bridging from a first-in-human study to a pathway to licence HIV/AIDS is still a catastrophic public health problem.  Recent estimates show 2.3 million new infections per year and 1.6 million deaths among the 35 million people living with the disease.  The problem is 95%+ in the developing world: young people, especially women and girls, are particularly vulnerable.  The highest risk in rich countries is from receptive anal intercourse, with both women and men involved

Although HIV/AIDS has become a largely treatable condition in rich countries, serious long-term complications are now emerging: cardiac, metabolic, mental health, cancer-related, accelerated ageing.  Prevention is therefore key.  A working vaccine still seems years away but another strategy is the use of ‘microbicides’, anti-HIV compounds applied to the genital areas to prevent infection during sex.

One such substance is called 5P12-RANTES.  It is among the most potent anti-HIV substances known, potentially safer than many alternatives, and much better at avoiding drug resistance.  Thanks to previous support from the Trust, a means of manufacture has been found opening the way to cheap manufacture even in some developing countries.  The proposed project by Professor Robin Offord and colleagues at the Mintaka Foundation will allow a potential major backer to trial it in rectal use; permit development of long-acting formulations for vaginal and rectal use; and further reduce production costs with a view to transferring manufacture to developing countries.
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Translation Award Hypoxic tumour radiosensitisation using a tunable, nitric-oxide-neutral oxygen-binding protein technology Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of 14 months.  GBM is characterised by low oxygen levels (hypoxia) which is known to worsen the prognosis for patients.  Radiotherapy (RT) and chemotherapy (CT) are each more effective aganist oxygenated cancer cells compared  to oxygen-deficient cells, and hypoxic tumour ceels are also more prone to recruit  new blood vessels and invade neighbouring tissues.

Omniox has identified a new approach to overcome hypoxia in GBM by delivering oxygen deep into the tumour.  Omniox' therapeutic candidate, OMX-4.80, is an oxygen-binding protein engineered to penetrate into tumours and release oxygen upon reaching areas that are hypoxic. 

Dr Stephen Cary from Omniox has received a Translation Award to test OMX-4.80 in patients to ensure it is safe, accumulates tumours, and reduces tumour hypoxia.  Ultimately, the team is developing OMX-4.80 to restore oxyten to improve RT and CT efficacy and extend the lives of patients with GBM.  If successful in GBM, OMX-4.80 is likely to benefit other cancer populations in the future.
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Seeding Drug Discovery Novel inhibitors of MAP4K4 (HGK), an acute therapy to prevent cardiac muscle cell death following myocardial infarction Heart disease is the most frequent source of death and disability worldwide, most especially as heart attacks (cardiac muscle cell death from obstructed blood flow to the heart). Its severity is due in part to heart muscle's inability to rebuild itself as most other tissues can. One potential strategy, to enhance standard therapies like “clot-busting” drugs and stents, is to suppress cell death directly by protecting the injured, jeopardized muscle cells.

Professor Michael Schneider at Imperial College London has identified the enzyme MAP4K4 as a key regulator of cardiac cell death and has devised novel, potent, selective drug-like inhibitors to protect human cardiac muscle grown in the laboratory. This Seeding Drug Discovery Award will enable the innovative use of human cardiac muscle grown from stem cells to pinpoint the molecules responsible for cardiac injury and will take the programme of research the essential steps further, towards the development of MAP4K4 inhibitors as clinically workable compounds
Seeding Drug Discovery Optimisation of a series of hits against trypanosome phosphofructokinase to give a lead for treatment of the neglected disease Human African Trypanosomiasis Human African Trypanosomiasis (sleeping sickness) is a neglected disease which is transmitted by tsetse flies. Without treatment death is inevitable and current drugs are poorly effective. Professor Malcolm Walkinshaw of the University of Edinburgh and colleagues are working on developing a new drug for sleeping sickness based on understanding the biology of the T. brucei parasite that causes the disease.

T. brucei gets its energy from the breakdown of glucose (glycolysis) obtained from host blood for survival. The proteins used for this process (so-called glycolytic enzymes) provide the parasite with its only source of energy (ATP molecules). The compounds already identified in this project have been shown to kill the parasite by specifically inhibiting glycolysis. High throughput screening against one of the glycolytic enzymes (PFK) identified three chemically different families of inhibitors each capable of killing T. brucei parasites. The objective of this project is to design and synthesise related compounds to improve potency so that very low (nanomolar) concentrations of compound are needed to kill parasites.
Anti-MRSA nasal product
Translation Award Development of a novel multi-valent, targeted treatment for serious Escherichia coli and Klebsiella pneumoniae infections Phico Therapeutics Ltd has developed a novel antibacterial platform technology, SASPject, which utilises an antibacterial protein, SASP, which disables all bacteria by inactivating their DNA; without active DNA, bacteria cannot survive or multiply.  The SASPject technology couples SASP with nano-delivery vehicles (NDVs).

NDVs are made from bacterial viruses (viruses that attack only bacteria), and Phico uses NDVs to selectively deliver SASP to those bacteria which are causing an infection. The unique way in which SASP works, by inactivating bacterial DNA even if it mutates, means that resistance is very unlikely to develop: any potential resistance that the bacteria could develop to the NDV’s themselves is addressed during development.  SASPject can potentially be used against any harmful bacteria but being able to target it to selected pathogens avoids damaging the normal human flora.  Uniquely, SASP could help to prevent the further spread of existing antibiotic resistance.  In this project, led by Dr Heather Fairhead at Phico Therapeutics plans to utilise and extend the company’s knowledge, experience and innovative techniques to produce a SASPject product that can be used intravenously to treat serious infections due to the Gram negative bacteria, E. coli and K. pneumoniae, including those which are multi-drug resistant.
Strategic Award Community for Open Antimicrobial Drug Discovery (CO-ADD) Multi-drug resistant (MDR) microbes are a serious health threat as the approval of new antibiotics has dropped alarmingly. To find new classes of antimicrobials, novel chemical diversity needs to be accessed. The Community for Open Antimicrobial Drug Discovery (CO-ADD) is an ‘open access’ compound screening initiative www.co-add.org. CO-ADD will uncover novel antibiotic and antifungal compounds from the untapped chemical diversity residing with synthetic organic chemists in academic laboratories in all countries.

  CO-ADD has established capacity for antimicrobial testing, hit-confirmation and validation, resistance determination, target identification, and ADME/T in one facility located at the University of Queensland, Australia. A focused initiative will benefit the antimicrobial research community and end-users by identifying new antibiotic and anti-fungal chemotypes, as well as providing valuable information on the physicochemical and structural properties of a compound required for antimicrobial activity.

The global reach of the initiative necessitates support from a visionary organisation committed to the advancement of human health worldwide. National academic and commercial funding models would not be in a position to support the scope of this project. CO-ADD will pioneer an ‘open access’ screening initiative to challenge conventional thinking on the antimicrobial discovery process.  They will determine if: i) there are novel antibiotic chemotypes in chemistry laboratories that have not been identified simply because they have never been tested, ii) the chemical space of compounds synthesised outside corporate collections differ significantly from libraries already screened, iii) an ‘open access’ approach to antimicrobial discovery targeting synthetic chemists can re-invigorate antimicrobial discovery.  CO-ADD will screen compounds from academic research groups from anywhere in the world for antimicrobial activity for free.
Seeding Drug Discovery Highly selective small molecule drug leads for use in blocking tumour epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) Many forms of breast cancer currently respond well to modern targeted treatments – where drugs are designed to inhibit individual protein "targets" in the cancer. But around one-in-five to one-in-ten breast cancers, termed "triple negative breast cancers", cannot be treated this way because no target responsible for this cancer has been identified.

These cancers have a higher rate of spread, are more likely to return following chemotherapy, and thus are more likely to become terminal.  Researchers at the biotechnology company BerGenBio have identified a novel target that is present in many triple negative breast cancers. The objective of this project is to develop two drug-like lead series against this new target and to develop potential new drugs for the treatment of triple negative breast cancer.
Pathfinder Award Effect of AP301, a synthetic peptide mimicking the lectin-like domain of TNFalpha, on PHA type 1b causing mutations in the amiloride-sensitive epithelial sodium channel (ENaC) This Pathfinder Award addresses the orphan disease pseudohypoaldosteronism type 1b (PHA type 1b), a life-threatening condition in which the sodium ion channel, ENaC, found in kidneys, colon, lungs, salivary and sweat glands has either reduced or no functionality.

Non-function of ENaC results in loss of sodium in the urine and faeces and severe salt imbalance in the body. Characteristic features are low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood. The disease usually presents in newborns who fail to thrive and suffer from severe dehydration; other symptoms are abnormal heartbeat or shock due to salt imbalance and recurrent lung infections due to accumulated fluid. The condition does not improve with age and patients require life-long salt supplements and special treatment to remove potassium.

AP301 is a small biological molecule known as a peptide, composed of 17 amino acids, which activates the normal form of ENaC. Aerosolised AP301 has recently been shown to reduce lung liquid levels in patients suffering from acute respiratory distress syndrome (ARDS).   The team at APEPTICO GmbH, in collaboration with the University of Vienna, will test whether AP301 activates ENaC into which the genetic defect causing PHA type 1b has been artificially introduced. The bioactivity of AP301 will be compared to that of a scrambled peptide, with the same 17 amino acids as AP301 but in a different sequence order, used as a control. If AP301 activates this defective ENaC, then it could be used to treat lung ailments of PHA type 1b patients.
Pathfinder Award Fetal haemoglobin (HbF) induction as a strategy to improve life quality in thalassemia: characterisation of HbF inducing products and preclinical models to predict therapeutic response Beta-thalassemia treatment can still be considered a major unmet medical need, indeed thalassemia is a disease without an adequate treatment. Survival is increased, even in patients needing transfusions, in comparison with few years ago in most countries, but the quality of life is still poor for many patients and the complication of frequent transfusions is a major problem.

The concept of improved quality of life and possibly increased survival trough increased fetal haemoglobin found widespread acceptance, but rather limited practical application for the lack of adequate drugs and lack of methods able to select the most appropriate patients.  A team from Rare Partners and the Department of Life Sciences and Biotechnology at Ferrera University, Italy aim to advance their knowledge and transfer preclinical findings to clinical application in a relatively short time.  Among the different drugs useful for management of thalassemia, the project team will focus their attention on those expected to be tested in clinical trials.
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Pathfinder Award Use of secretion inhibitors as novel antifungal drugs Meningitis due to the fungal pathogen Cryptococcus neoformans is rampant in Africa. Nearly one third of meningitis patients have shown treatment failure or resistance to currently available antifungals, demonstrating a tremendous need for the identification and development of new drugs to combat this fungal infection

A Pathfinder Award to Prof. Marcio L. Rodrigues (Centre for Technological Development in Health, Fiocruz, Brazil), in partnership with the Institute of Pharmaceutical Technology of Farmanguinhos will provide pilot funding for the search of antifungals with the ability to inhibit the cellular traffic of key virulence factors used by C. neoformans to cause damage to host cells.
Pathfinder Award Development of new leads for animal trypanosomiasis This programme builds on a DFID funded drug discovery and development collaboration between the University of Dundee’s Drug Discovery Unit and the Global Alliance for Livestock Veterinary Medicines (GALVmed) to continue medicinal chemistry optimisation and development of a novel lead compound series as a veterinary drug for the treatment of Animal African Trypanosomiasis in cattle.

The aim is to deliver a new treatment for this parasitic disease which is spread predominantly by tsetse flies in sub-Saharan Africa. It causes serious economic losses in in important livestock including cattle, goats and camels as a result of reduced productivity from clinical disease with severe anaemia, emaciation and mortality. Of particular importance is the reduction in draught power or traction of infected animals which leads to a corresponding reduction in the ability to prepare (plough) fertile land for production of important crops. In the >10 million km2 of fertile land across 40 African countries infested with tsetse flies, which are inhabited by >56 million cattle and >70 million small ruminants, more than 3 million cattle die annually of the disease. This is despite the use of more than 150 million annual doses of existing commercially available animal drug treatments (trypanocides).These currently used trypanocides (including diminazene and isometamidium) were discovered more than 50 years ago and have limitations with respect to toxicity, safety and increased emergence of drug resistance. No vaccines against the disease are available nor likely to be developed in the near future due to immune evasion via antigenic variation with trypanosomes. There is therefore a clear and urgent need for novel pharmaceutical livestock products for the treatment and prophylaxis of Animal African Trypanosomiasis.
Retinoic acid receptor a agonists for the treatment of Alzheimer's disease
Translation Award Phase I trial: t4 immunotherapy of squamous cell carcinoma of head and neck (SCCHN)
Head and neck cancer causes over 2,800 deaths in the UK each year. Unlike many other cancers, the primary cause of morbidity and mortality is locally advanced disease, rather than metastasis.

To address this, Dr John Maher from King’ s College London has received a Translation Award to test a novel treatment called T4 immunotherapy. T4 immunotherapy is a novel cell therapy in which patient immune cells (T-cells) are modified using a safe virus to express two new fusion proteins and are then expanded in culture  for 2 weeks.  The first fusion protein is a chimeric antigen receptor (CAR) that enables T-cells to recognize and kill tumour cells that express any of a range of ErbB receptor pairs. The second fusion protein facilitates the expansion process, rendering manufacture of cell products more robust. To maximise effectiveness and minimise risk, T4 immunotherapy will be injected directly into the tumour at a single setting, under ultrasound guidance. The primary focus of the study is the assessment of safety of this approach but several secondary objectives will also be investigated, including a preliminary assessment of effectiveness.
Salmonella Typhimurium
Seeding Drug Discovery Structure-aided discovery of CaMK1D kinase inhibitors as targeted therapeutic agents for breast
Kinases are important targets for blocking cancer progression.  However, many remain to be exploited.  For example, no drugs are yet available to specifically inhibit any kinase which is switched on by a regulatory protein called calmodulin. Nonetheless, faulty expression of these “CaMK” enzymes is now thought to play a key role in breast cancer progression.

The Wellcome Trust has funded the CAMSEED consortium to discover small molecule inhibitors for a CaMK protein involved in basal-like breast cancer.  The three dimensional structure of this target has been solved by the Structural Genomics Consortium and Professor Stefan Knapp at the University of Oxford.  Interactions with small molecules are being screened by Professor Michael Overduin’s lab at the University of Birmingham using superconducting magnets and high throughput robots at the national HWB-NMR facility.  The design of improved inhibitors that can enter cells and selectively block the oncogenic state is being led by Professor Peter Fischer at the University of Nottingham, with Colin Kenyon at CSIR, Pretoria designing deuterated analogs for enhanced activity.  The result of the two year project is expected to be a set of lead molecules for development as potential therapeutic agents for breast cancer, and may yield a new approach for using nature’s own inhibitory mechanisms to block cancer-causing kinases.
Salmonella Typhimurium
Translation Award Bispecific small molecule antibody conjugate for hormone-refractory recurrent prostate
The Wellcome Trust has funded a research team at the California Institute for Biomedical Research (Calibr) lead by Dr Chanhyuk Kim to develop a novel immunotherapy to treat prostate cancer. Prostate cancer is the second most common cancer in men and kills 250,000 men per year worldwide. 

There is currently no effective treatment for prostate cancer which has progressed to hormone-refractory prostate cancer (HRPC).  Patients with HRPC on average only live 1-2 years before succumbing to the disease.  In a search for new treatments, the team at Calibr have created a drug that engages the patient’s immune system to seek and destroy prostate tumor cells. This technique is a promising alternative to chemotherapy.  The properties of this novel protein conjugate enable it to efficiently target malignant HRPC cells and recruit a robust anti-tumor immune response.  Preclinical research demonstrates that this therapy effectively eliminates tumor cells both in vitro and in mouse models.  The primary goal of the proposed research is to develop this technology through safety studies and initiate pilot scale manufacturing.  This will enable preparation of an investigational new drug application and serve as a catalyst for an industry partnership to carry out a Phase I clinical trial, thereby offering this innovative new therapy to patients with HRPC.
Salmonella Typhimurium
Seeding Drug Discovery Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications. However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”.

These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion.  Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time.  Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate,  which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population.
The Novartis Institute for Tropical Diseases: Malaria Drug Discovery
Seeding Drug Discovery Discovery of new leads for the treatment of Human African Trypanosomiasis Human African Trypanosomiasis (HAT) is a deadly disease caused by the T. brucei parasite that is prevalent throughout 36 sub-saharan African countries. The most serious form of the disease occurs when the parasite enters the Central Nervous System (CNS), causing significant neurological damages that are lethal if the infection is not treated. The current treatments cannot be administered orally and have serious safety liabilities which make them largely inadequate for mass administration and disease elimination programs.

The Novartis Institute for Tropical Diseases (NITD), an integrated part of the Novartis Institutes for BioMedical Research, is a drug discovery organization dedicated to the identification and early development of novel treatments for neglected tropical diseases. Through several chemical libraries screens, NITD and its collaborators have identified several thousands of new compounds (hits) potently active against the T. brucei parasite. The proposed research aims to triage and characterize these hits with the objective of identifying new compound classes compatible with their target product profile of an effective, safe, cheap and orally available new HAT treatment.
Retinoic acid receptor a agonists for the treatment of Alzheimer's disease
Translation Award A systematic programme to develop and evaluate the best candidate treatments for repositioning as therapies for Alzheimer’s Disease (SMART-AD)
This innovative programme will identify drug candidates for repositioning in Alzheimer’s Disease (AD).  Professor Clive Ballard and colleagues at King's College London, will compare the transcriptional signature of AD with the signatures of up to 4000 drugs with established safety in man to identify 100 candidates with the most promising therapeutic potential.

State of the art gene profiling will be used to determine the ability of the candidates to modify the expression of disease-associated transcripts in hippocampal neurons, with the best 20 drugs going forward to test for biological efficacy in in-vitro assays for a wide-range of pathogenic mechanisms implicated in AD. The six agents with the most favourable impact will then be evaluated in the best rodent model of AD to obtain the proof-of-principle evidence that would support a clinical program. Importantly assays used will measure a range of key pathological and behavioural outcomes, as well as determining the drugs impact on disease-associated transcriptional changes. Each stage will be overseen by an independent expert panel to ensure drug selection is rigorous and appropriate for AD. The overall aim of this programme of research is to identify the best candidate to be taken forward to clinical trial in people with AD.
Salmonella Typhimurium
Pathfinder Award Better drugs for cryptosporidiosis: hit-to-lead studies for confirmed MMV screening Cryptosporidium parasites are intracellular and related to malaria parasites, but the infection is restricted to the intestinal epithelium.

This award is to fund the collaboration between the University of Vermont and Medicines for Malaria Venture (MMV) to determine if assets from the MMV Malaria Box have the pharmacologic characteristics required for a potential effective anti Cryptosporidium  drug that differs from those needed to treat systemic infections.
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Seeding Drug Discovery Apolipoprotein E4 as a therapeutic target for Alzheimer's disease:  Identification of small molecule structure correctors to prevent apolipoprotein E4-associated neuropathology Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). Indeed, one in four people carry the apoE4 gene, whereas 65 to 80% of all AD patients have at least one copy of apoE4.

The apoE protein, which functions in the normal maintenance and repair of nerve cells, occurs in two major forms: apoE3 and apoE4. ApoE3 is often referred to as the normal form, while apoE4 differs from apoE3 by the change of a single amino acid residue (1 out of 299). This single change causes apoE4 to have an abnormal structure and function. As a result of this abnormal structure, the production of apoE4 in nerve cells sets off a chain of events that, over time, leads to neuronal degeneration and cell death. Believed to be an intruder, apoE4 is attacked by a protease enzyme and cut into smaller toxic fragments. These fragments then wreak havoc on many vital structures in the cells.  Robert W Mahley, MD, PhD, and his colleague Yadong Huang, MD, PhD, have identified small molecules that correct the abnormal structure of apoE4, mitigating its harmful effects by converting it to the functionally normal apoE3. The Trust has awarded $2.5 million over two years to Dr Mahley and the Gladstone Institutes to develop new chemical entities that target apoE4 in the brain in order to prevent the development of AD. Under the award, Gladstone will collaborate with San Francisco-based chemoinformatics company Numerate for chemistry expertise.
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Pathfinder Award Development of human induced pluripotent stem cells (iPSCs) in patients with neurodegeneration with brain iron accumulation (NBIA) A Pathfinder Award to Dr Michael Hutton at Eli Lilly, in partnership with Professor John Hardy at UCL, will provide pilot funding for this Industriy-Academic partnership to work on the rare disorders termed Neurodegeneration with brain iron accumulation (NBIA).

This is a group of rare, severe neurological disorders that are characterised by parkinsonism, cognitive decline and dystonia.  The Award will fund the development of human induced pluripotent stem cells (iPSCs) cells offers a way to develop in vitro models of these diseases in the laboratory, without exact knowledge of the disease mechanism(s). The cell characteristics will enable these models to be amenable to drug treatment from the array of therapeutic compounds held by Lilly going forward.
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Pathfinder Award Developing a transformative therapy for inherited homocystinuria by correcting the misfolding of cystathionine beta synthase disease alleles This Pathfinder Award brings together world-class researchers from Pfizer Inc.’s Rare Disease Research Unit in Cambridge, MA (US), including Dr Christine Bulawa of Pfizer, and the Structural Genomics Consortium (SGC) in Oxford (UK), including Dr Wyatt Yue, to study cystathionine beta synthase (CBS) deficiency.  CBS deficiency is a rare genetic disorder in which affected people cannot process the amino acid methionine.

In many patients, a genetic defect causes the CBS enzyme to lose its optimal three-dimensional shape and prevents the enzyme from functioning properly.  This leads to the build up of homocysteine in the body, causing an array of symptoms including early cardiovascular disease. The current standard of care is to reduce homocysteine levels by a methionine-restricted diet or supplementation with vitamin B6, a cofactor for the CBS enzyme. However, this does not treat the underlying cause of the disease, and many patients do not respond to these treatments.   During the course of this collaborative research, scientists at Pfizer and SGC aim to develop biochemical and molecular tools to facilitate discovery of a potential drug that restores the optimal shape and function to the defective CBS protein, thereby treating the root cause of the disease.
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Pathfinder Award A preclinical feasibility study using recombinant homogentisic acid dehydrogenase as an enzyme replacement therapy for alkaptonuria There are over 6000 known rare diseases and most are of genetic origin. One such condition is alkaptonuria (AKU), which is caused by a faulty enzyme.  This means patients produce a chemical called homogentisic acid (HGA). Some HGA leaves the body in urine. The rest builds up in body tissues, eventually causing serious health problems.

Some of this HGA is converted into a black pigment. Over time this black pigment stains joint tissues, including bone and cartilage, causing early onset, severe arthritis. This is why AKU is also known as ‘black bone disease’. Patients also suffer severe pain and heart disease. Most AKU patients become severely disabled as life progresses and many of them end up wheelchair-bound. There is no known cure for AKU and current treatment relies on pain management and joint replacement. This project's key objective is to test the idea of enzyme replacement therapy (ERT). We will make human enzyme in bacteria (as a method of manufacture) and then test it in mice with AKU. If this reduces the effects of AKU in the mice, then it might be possible to treat this debilitating disease for the first time.  This is a collaboration between Protein Technologies Ltd and the University of Liverpool.
Clinically practical two- and three-dimensional ultrasonic elasticity imaging
Seeding Drug Discovery Fragment-based lead discovery against the protein-protein interaction between Aurora A and TPX2 for the treatment of cancer The Wellcome Trust has awarded over £2.3 million to Chris Abell, John Skidmore and co-workers at the University of Cambridge to use fragment-based approaches for the generation of molecules which disrupt the interaction between the kinase Aurora A and the regulatory protein TPX2.

Such compounds are expected to have utility in the treatment of a number of solid and haematological cancers, with one particular focus being reversal of taxane resistance in solid tumours. The project will generate lead compounds suitable for screening in cancer cell-lines and animal models to further validate the target and will also provide leads for future optimisation towards a drug. This funding follows on directly from an ongoing Strategic Award pioneering the use of fragment-based approaches against protein-protein interactions, which used biophysical screening and X-ray crystallography to generate the fragment leads for the planned project.
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Translation Award Treatment of obesity with the pancreatic polypeptide analogue PP 1420 Obesity is a massive health problem worldwide. Currently, no medication is safe and effective. Imperial College have developed a new drug for obesity called PP 1420, which uses the body’s natural satiety system for controlling appetite.

It is given as an injection once a day and works by suppressing appetite. In a previous study, Imperial tested PP 1420 for the first time in healthy volunteers, and found that it was both safe and without side effects. The Wellcome Trust are now supporting a further study of PP 1420 to show that PP 1420 is able to reduce food intake and body weight when multiple doses are given.  This study if headed up by Professor Sir Stephen Bloom
Seeding Drug Discovery A stream-lined lead optimization project with the potential to deliver first in class small molecule inhibitors of Respiratory Syncitial Virus (RSV) RSV is one of the most important respiratory pathogen with 64 million infections and 160,000 deaths estimated worldwide annually. RSV infection is responsible for more infant hospitalizations than other viral infections such as influenza.

Susceptible populations are premature infants, children, transplant patients, the elderly and people of all ages with heart failure and lung disease. In addition, severe infection in infancy is linked to the later development of asthma. In the elderly in the US it was shown that RSV infection caused 177,500 hospital admissions and 14,000 deaths over a period of 4 years.  Hospitalization costs alone were estimated at more than $1 billion.  re:VIRAL Ltd is focused on development of novel antiviral treatments for RSV.  The Company has been granted an Seeding Drug Discovery award from the Wellcome Trust to develop novel small molecule RSV fusion inhibitors up to completion of  preclinical studies.  This project is a collaboration between re:VIRAL Ltd. and the University of Sussex Drug Discovery group. The key goals of this project are to identify a drug candidate suitable for progression into studies in man and novel back compounds with the ambition of developing the first approved therapy for RSV.
Translation Award Development of novel small molecules for the treatment of antibiotic resistant bacterial infections Due to a dearth of new antibiotics in development, resistant bacteria are presenting a growing challenge to patients, physicians, and health organizations, resulting in higher patient morbidity and mortality as well as increased health system costs.

For example, the alarming spread of newly emerging “CRE” (Carbapenem-Resistant Enterobacteriaceae) “super-bugs” threatens to become a global crisis.   With an investment of $8.9M from the Wellcome Trust Translation Fund, VenatoRx is developing new antibacterial therapeutic products to address multi-drug resistant gram negative bacteria, including resistant E. coli, K. pneumoniae, and P. aeruginosa, important causative agents for complicated urinary tract infections, complicated intra-abdominal infections and many types of serious pneumonia. 
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Seeding Drug Discovery Next generation broad-spectrum antifungal treatment – development of a fungal proton pump inhibitor drug candidate Fungal infection is a serious problem, especially for critically ill patients. There is an increase in the number of infections that cannot be treated with the medicines available today. This is in part caused by the increased number of infections with fungi that are resistant to existing drugs but also due to the appearance of treatment resistant rare types of fungus and the increased use of immunosuppressants to treat cancer and transplant patients.

The Wellcome Trust has funded Pcovery to develop a new drug with a novel mechanism of action for the treatment of serious fungal infections. The project will target a specific protein that is distinct for fungal cells, essential for fungal survival, and highly conserved across a number of fungal species. The hope is to identify a drug like compound, which will inhibit the function of the target protein and kill off the fungi without affecting the patient. Due to this novel mechanism of action it is expected that the drug will be active against fungi that are resistant to other antifungal drugs. It is also anticipated that the drug will have few side effects.
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Seeding Drug Discovery Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions.

The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Using two different approaches small molecules have been identified that bind to RAS at the same point of contact as the anti-RAS VH. The Seeding Drug Discovery  Award will be used to develop these hits through to leads and ultimately the identification of a preclinical development candidate.
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Seeding Drug Discovery Design and optimisation of new chemical entities that prevent the neurotoxic oligomerization and misfolding of both β-amyloid and tau proteins: A disease modifying therapeutics approach for Alzheimer’s Dementia Wellcome Trust has awarded a grant to TREVENTIS Corporation to discover a disease-modifying drug for the treatment of Alzheimer's disease (AD). Numerous studies support the causative role of β-amyloid (Aβ) and tau in the aetiopathogenesis of AD.

These proteins tend to abnormally "clump" (protein misfolding) and give rise to neurotoxic aggregates of β-amyloid (plaques) and tau ("tangles"), the pathological hallmarks of AD. In vitro studies have identified that Aβ can be neurotoxic when in small aggregates. Since disease-modifying drugs represent the most desirable therapeutic approach to AD, protein misfolding of Aβ and tau represents a potential target in the rational design of a drug. The ultimate goal of this research is to discover a disease-modifying new chemical entity for the treatment of AD that is efficacious and safe. This goal will be achieved by optimizing a class of small organic molecules capable of binding to both β-amyloid and tau, blocking their misfolding. A new series has recently been identified that are drug-like, potent anti-aggregants and penetrate the Central Nervous System. Funding under this award will enable the discovery of a lead candidate with completed pre-clinical pharmacokinetic and toxicology package.
Seeding Drug Discovery Inhibition of small-conductance Ca2+-activated potassium (SK) channel as a novel concept for the treatment of atrial fibrillation Atrial fibrillation (AF) is the most common cardiac arrhythmia (irregular heart beat), affecting an estimated 4.5 million people in the EU. AF mainly affects the elderly population and lifetime risk for developing AF is 25% for individuals over 40 years of age.

AF is associated with impaired quality of life, increased rate of hospitalisation, and increased risk of stroke and death.  The Wellcome Trust has funded the Danish Biotech company Acesion Pharma to develop a novel pharmacological treatment for the acute cardioversion of AF to normal heart rhythm (sinus rhythm). The project aims to identify a compound that selectively blocks the so-called SK channel, a novel biological target for AF treatment.

Currently used medicines against AF are only moderately effective in cardioversion and have risk of serious adverse effects. There is therefore a significant medical need of new treatment options with better safety profile and higher efficacy. Based on Acesion Pharma’s existing know-how on SK channels and compounds blocking this ion channel, it is envisaged that such a compound could become a safer and more efficacious drug for AF.
Seeding Drug Discovery GSK Diseases of the Developing World Discovery Engine GSK's Tres Cantos Medicines Development Campus in Madrid, Spain has received a commitment from the Wellcome Trust to provide up to £5m in support of its open approach to discovering and developing urgently needed new treatments for diseases of the developing world.

The funding will move early-stage research to the next level, to find new medicines for diseases such as TB, malaria, Leishmaniasis and sleeping sickness. Scientists from around the world will work in collaboration with GSK drug discovery experts at its facility in Tres Cantos, Madrid which also houses GKS's Open Lab. The funding will provide the opportunity to progress the most promising projects underway by independent scientists at the Open Lab and from GSK's own research portfolio. The overarching goal of the investment is to develop two high-quality experimental drugs over the next five years.
Strategic Translation Award Administration of sNN0029 (VEGF) using an implanted drug delivery system for the treatment of patients with Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis (ALS)  is a deadly disease that causes death of nerve cells (motor neurons) that are normally used to control breathing, swallowing and movements, e.g. of limbs. The disease affects 200,000–300,000 patients worldwide and approximately 90% of patients with ALS die within 5 years of diagnosis.

sNN0029 is a drug that contains a naturally occurring protein called VEGF that has been shown to have disturbed expression in the central nervous system of ALS patients, as well as promoting survival of motor neurons in relevant rodent models.  Based on these findings, NeuroNova AB – a Swedish subsidiary of Newron Pharmaceuticals in Milan, Italy – has developed a therapy to directly deliver VEGF into the brain using a drug delivery system which is placed underneath the skin. The company has completed a three month phase I/II safety and tolerability study of this therapy in ALS patients. The Wellcome Trust is now providing a programme-related investment to complete a phase I/II trial to evaluate safety and efficacy of higher doses of sNN0029 in patients with ALS.
Seeding Drug Discovery A Centre of Excellence for lead optimisation for diseases of the developing world There is an urgent need for new drugs to treat the major infectious diseases of the developing world, such as TB, malaria and African sleeping sickness. However, despite significant efforts in early stage drug discovery, there is a bottleneck when it comes to the lead optimisation stage of molecules targeting these diseases.

To address this need Professor Paul Wyatt and colleagues at the Drug Discovery Unit (DDU) at the University of Dundee, with joint funding from the Wellcome Trust and Bill & Melinda Gates Foundation, are establishing “A Centre of Excellence for Lead Optimisation for Diseases of the Developing World.” The initial focus will be on TB, where the strategy is to identify a portfolio of TB Lead Optimisation projects through the DDU’s involvement with the HIT-TB consortium and TB Drug Accelerator Program which are working to generate leads through their screening programmes. The DDU as part of HIT-TB is already identifying and optimising multiple hit series that could be taken up by the team.
Seeding Drug Discovery Novel small molecule inhibitors of metallo ß-lactamases for the treatment of multi-drug resistant Gram-negative infections Multi-drug resistant Gram-negative bacteria account for most hospital infection worldwide (e.g.  causing 25,000 deaths in Europe and extra healthcare costs/productivity losses of >€ 1.5 billion/year).

One of the most effective treatments is the use of carbapenem antibiotics. However, their usefulness is becoming increasingly compromised due to the rise of clinical resistance associated with the spread of genes encoding various metallo ß-lactamase (MBL) enzymes, primarily the carbapenemases NDM-1, VIM-1/VIM-2 and IMP-1.

The Trust has awarded Dr. Marc Lemonnier, CEO of Antabio, €4.7m over 3 years to fund the development of a novel, safe and efficacious pan-inhibitor of bacterial metallo ß-lactamases. The project team being led by Principal Investigator Dr. Marc Lemonnier, will develop drugs inhibiting these MBL enzymes, thereby returning carbapenems to full clinical effectiveness. The project will develop current leads to preclinical candidate nomination. It is envisaged that hospitalised patients suffering from complicated Gram-negative infections will be treated with a combination of Antabio’s new inhibitor coadministered with a carbapenem.

This therapeutic concept has been successfully proven by existing beta-lactam/ serine beta-lactamase inhibitor combinations such as Augmentin (Amoxycillin/Clavulanic acid). Since these combinations will not work against bacteria that are MBL producers, the medical need for MBL inhibitors remains critical. A beneficial feature of this paradigm is that oral activity is not required – carbapenems are taken intravenously, so a newly developed inhibitor can be coadministered through that route. This regimen simplifies the research and greatly increases the possibilities for success. A successful drug will alleviate patient suffering and reduce antibiotic failure in the clinic.
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Translation Award First in Human clinical trials for SMT19969: A novel antibiotic for the treatment of Clostridium difficile infection Hospital acquired bacterial infections continue to be a significant burden to the healthcare system and to patient welfare due to ever increasing rates of antibiotic resistance and the rise in prevalence of emerging and hard to treat infections.

 One of the most important of these, Clostridium difficile, is a typically harmless bacteria that under certain conditions can cause a life-threatening infection of the colon. In particular, C. difficile infection (CDI) is associated with antibiotic use, which can cause an imbalance in the healthy bacterial population of the gut resulting in an overgrowth of C. difficile.  There are estimated to be around 900,000 cases of CDI each year across North America and the EU and the infection now accounts for >80% of deaths due to gastroenteritis. Of particular concern are outbreaks due to hyper-virulent strains of the bacteria that are responsible for more severe forms of the disease. Antibiotic choices for CDI are limited and of sub-optimal efficacy with up to  30 per cent of patients suffering at least one recurrence of the infection. Each recurrence  tends to be more severe and is associated with increased risk of further infection. Combatting recurrent disease remains the central issue in achieving effective therapy for this life threatening infection.

SMT19969 is a novel antibiotic being developed by Summit Corporation PLC for the specific treatment of CDI. SMT19969 shows high levels of selectivity for C. difficile whilst having minimal effect on the normal healthy gut bacteria, which is expected to result in a significant healthcare benefit by reducing rates of recurrent disease. Preclinical development was funded by a Wellcome Trust Seeding Drug Discovery award. With continuing support via a Translation Award to Summit Corporation PLC  the company is now undertaking Phase I first-in-man safety studies and Phase II efficacy trials.
Clinically practical two- and three-dimensional ultrasonic elasticity imaging
Seeding Drug Discovery Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics.

IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction. The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.
Seeding Drug Discovery Small molecule inhibitors of the anti-apoptotic FLIP-FADD protein-protein interaction for the treatment of non-small cell lung cancer In most organs and tissues, old cells are constantly dying and being replaced by new cells. This balance is critical for normal organ/tissue function and is maintained by a balance between new cells being created by cell division and old cells dying by a process known as "apoptosis".

One of the key characteristics of cancers is that the old cells do not die efficiently by apoptosis and therefore accumulate giving rise to a tumour that ultimately disrupts organ function.  This block in apoptosis is also a major problem when it comes to treating cancers as the effectiveness of chemotherapies and radiotherapies usually rely on their ability to activate this type of cell death.  Professor David Haighıs team at Queenıs University of Belfast have identified an intra-cellular protein called "FLIP" that plays a critical role in preventing the death of cancer cells treated with chemotherapy and radiotherapy. This protein plays a prominent role in increasing the resistance to therapy in a number of types of cancer,  including non-small cell lung cancer, which is a particularly drug-resistant cancer and is the focus of this proposal. The project team plan to generate drugs to block FLIP's function and thereby overcome drug resistance and improve the therapeutic management of patients with this disease.
Seeding Drug Discovery Perforin Inhibitors for the prevention of allogenic bone marrow stem cell transplant rejection Perforin is a novel and tractable target, the inhibition of which would address significant unmet need in clinical allotransplantation and potentially, a number of other human disorders. An immunosuppressant targeting perforin would provide the first-ever therapy focussed specifically on one of the principal cell death pathways leading to transplant rejection.

The Trust has awarded AU$6.8m over three years to Professor Joe Trapani (Peter MacCallum Cancer Centre), Professor Bill Denny (University of Auckland), Professor James Whisstock (Monash University) and Professor Geoff Hill (Queensland Institute for Medical Research) for the development of small molecule inhibitors of perforin that could lead to more prevention of allogeneic bone marrow stem cell transplant rejection and therefore increase survival rates for many forms of cancer. The team led by Professor Joe Trapani, have recently developed three classes of compounds which have been shown to block the action of perforin. Under the Trust funding the team will continue to characterise and improve on these compounds. These inhibitors will be assessed in specific models and then progressed into clinical candidates that could be ultimately assessed in drug trials for indications with significant unmet clinical need.
11b-Hydroxysteroid Dehydrogenase Type 1 (11b-HSD1) Inhibition: tissue-specific control of cortisol action
Seeding Drug Discovery 11b-HSD1 inhibition for disease modification and symptom control in Alzheimer's disease Professor Brian Walker, Professor Jonathan Seckl and Dr Scott Webster, University of Edinburgh have identified 11b-HSD1 as a crucial amplifier of glucocorticoid action in liver, adipose tissue and CNS, have shown its pathophysiological significance in obesity, and have provided preclinical and clinical 'proof of concept' that 11b-HSD1 inhibition improves both Metabolic Syndrome and cognitive function in ageing.

Although their work has fuelled intense commercial interest in developing 11b-HSD1 inhibitors for metabolic indications, including type 2 diabetes, the opportunity to improve cognitive function has not yet attracted pharmaceutical companies.  Under the latest round of funding, they will select the optimal clinical candidate and aim to progress these to Phase I clinical trials aiming at a memory improvement.
Seeding Drug Discovery Development of a type B lantibiotic for treatment of Clostridium difficile infection C. difficile infection (CDI) has increased in incidence and severity through the last decade to become the major cause of mortality amongst nosocomial infections. Currently, there are very few therapeutic options for CDI and recurrence of disease after initial successful therapy is a major health problem and burden to healthcare systems.

Novacta Biosystems Limited has embarked on development of a class of agents called type B lantibiotics which inhibit bacterial cell wall biosynthesis. The agents have promising properties for treatment of CDI in that given orally they are stable in the gastro-intestinal tract and not absorbed, their mechanism of action provides a good resistance prognosis and they have low toxicity. Starting with the discovery of a new lantibiotic, deoxyactagardine B, a combination of biosynthetic modification at the genetic level and semi-synthetic chemistry yielded NVB302, a drug candidate with excellent activity against C. difficile and very little activity against the predominantly Gram-negative gut flora. This selectivity is believed to be important to allow the colonic flora to restore a barrier to re-infection.

NVB302 is currently undergoing a phase I clinical trial in healthy volunteers.
Retinoic acid receptor a agonists for the treatment of Alzheimer's disease
Seeding Drug Discovery Identification of retinoic acid receptor b agonists for the treatment of spinal cord injury There are as yet no effective treatments for spinal cord injuries (SCI). The Trust has awarded £3.6 million  to Dr Jonathan Corcoran, Dr Barret Kalindjian and Professor Thomas Carlstedt for the development of orally available small molecules for the treatment of SCI.

Researchers led by Dr Jonathan Corcoran have identified a novel signalling mechanism - the retinoic acid receptor b (RARb) signalling pathway - that can be stimulated in models of SCI leading to axonal outgrowth and functional recovery. The pathway is activated by small molecules known as retinoids and leads to the modulation of various proteins that are known to be involved in axonal outgrowth. The award will allow the identification of novel RARb agonists which can be given orally to patients with SCI. Their use will be demonstrated in rodent models of SCI, and the work will ultimately lead to a clinical trial in human avulsion injury, which is one of many types of SCI.
KU Leuven
Seeding Drug Discovery Discovery of new drugs for the prophylaxis and treatment of dengue virus infections in humans The dengue virus is endemic in most tropical and sub-tropical regions around the world, predominantly in urban and semi-urban areas.  According to the World Health Organization 2.5 billion people, of which 1 billion children, are at risk of dengue infection.

An estimated 50 to 100 million cases of dengue fever, half a million cases of severe dengue disease and more than 20 000 deaths occur worldwide each year. Dengue is a leading cause of hospitalization and death amongst children in regions where dengue is present.  There is no vaccine, nor a specific treatment or prophylaxis for dengue. 

With Welcome Trust funding, Professor Johan Neyts (Rega Institute) together with the Centre for Drug Design and Discovery (CD3) at the University of Leuven(KULeuven) identified a novel class of potent inhibitors of dengue replication.  The lead compounds in this series elicit activity against all four dengue serotypes with a large therapeutic window. This class of small molecule inhibitors has a good ADME-Tox profile and targets the virus via a unique mechanism.  Furthermore the barrier to resistance is high and once obtained, the fitness of such variants is low.  The project is now in a lead optimisation phase.
Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer
Seeding Drug Discovery Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix.

LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer. Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.See our video: BRAF and cancer: collaborative drug discovery
Discovery and development of novel small molecule inhibitors of the human cardiac acetylcholine activated current (IKACh) for the treatment of atrial fibrillation
Seeding Drug Discovery Novel small molecule inhibitors of the human cardiac acetylcholine activated current (IKACh) for the treatment of atrial fibrillation
Atrial fibrillation (AF) is an abnormal, disorganised, cardiac rhythm that originates in the upper chambers (atria) of the heart. It is the most common sustained cardiac arrhythmia encountered in clinical practice, with around 12 million sufferers worldwide and is gaining in clinical importance as the population ages.

AF is clinically significant because it contributes to the incidence of stroke and overall cardiovascular morbidity and mortality. Patients with AF have a five-fold increased risk for stroke; indeed, in the US approximately 15-25 per cent of all strokes can be attributed to AF. The treatment of AF is controversial and often problematic. Whereas electrical cardioversion restores sinus rhythm in many patients with AF, the maintenance of sinus rhythm often requires chronic treatment with anti-arrhythmic drugs. Although there is a consensus amongst cardiologists that sinus rhythm control with anti-arrhythmic drugs is the preferred and most effective treatment of AF, none of the existing drugs are able to maintain rhythm without significant negative side effects. Consequently new anti-arrhythmic drugs are desperately needed.  Xention Limited has received Seeding Drug Discovery funding to develop an orally active drug for the safe and effective treatment of AF with a substantially improved safety profile compared to current therapies.
Manchester-St Georges logos
Seeding Drug Discovery Allergen Delivery Inhibitors:  Preclinical evaluation Allergen Delivery Inhibitors offer the potential to combine alleviation of asthma with allergy prophylaxis using small molecule inhaled therapy.  Researchers at St George’s, University of London and the University of Manchester have employed structure-based drug design to develop inhibitors that selectively target house dust mite cysteine peptidases, enzymes that make significant contributions to the development, maintenance and escalation of allergic diseases including asthma. The programme’s candidate drug (CD 1) displays in vivo efficacy in animal models with a good duration of action when delivered to the airways. CD 1 is supported by several developable back-up compounds from chemically distinct and mechanistically distinct series. A patent portfolio is being created and Innovations is seeking a development and commercialisation partner for this programme.
Watch a short video in which the researchers explain their work
Seeding Drug Discovery Discovery and development of novel glioblastoma treatment that selectively reduces Bmi-1 expression in tumour stem cells BMI1 is a well-established oncogene that has been shown to be over expressed in tumour cells and necessary for cancer stem cell survival. PTC was awarded funding through the Wellcome Trust Seeding Drug Discovery initiative to identify novel small molecules that target BMI1.

It is widely accepted that a subpopulation of tumor cells, possessing intrinsic chemo-resistance and expressing many characteristics of normal stem cells, is responsible for treatment failure and relapse across multiple tumor types. BMI1 is a transcriptional repressor necessary for efficient cell division necessary for the renewing of adult hematopoietic stem cells as well as adult peripheral and central nervous system stem cells. BMI1 is widely over-expressed in human cancers and is critical in the development of glioblastomas, leukemias, lymphomas, and lung cancers. The level of BMI1 protein is positively correlated with disease grade and poor prognosis. By inhibiting BMI1 protein function and levels, PTC is targeting the resistant cancer stem cell fraction within tumours. 

PTC has identified compounds that potently reduce the levels of endogenous BMI1 protein in multiple cell lines at low nanomolar concentrations. Consistent with the function of BMI1, PTC?s compounds preferentially kill tumor cells, and in particular tumor stem cells, sparing normal primary progenitor cells.  PTC?s compounds selectively decrease the level of BMI1 in vivo on oral dosing in pharmacodynamic xenograft models of several tumor types. At higher doses of compound, this inhibition resulted in a nearly total control of tumor growth in multiple xenograft models of fibrosarcoma, glioblastoma, and leukemia. The program is currently in late lead optimization with the goal of identifying an orally available Development Candidate for the treatment of chemotherapy- and radiation-resistant cancers.
Seeding Drug Discovery Novel bacterial DNA synthesis inhibitors for the treatment of nosocomial infections caused by multi-drug resistant Gram-negative bacteria PTC Therapeutics, Inc. (PTC) has been awarded funding from the Seeding Drug Discovery initiative for a programme targeting the treatment of infections caused by multidrug-resistant Gram-negative bacteria.  PTC has identified a novel structural class of molecules that selectively inhibit bacterial DNA synthesis and have bactericidal activity.

These molecules are predominantly active against Gram-negative bacteria although several analogs in the series also have activity against Gram-positive species, including methicillin-resistant S. aureus (MRSA). The PTC compounds are potent against Gram-negative bacteria that are resistant to marketed antibiotics. Representative compounds have good pharmaceutical properties and are efficacious in murine models of systemic E. coli infection. The anti-infective program at PTC is currently in lead optimization and advancing towards identifying a development candidate as a potential first-in-class drug for the treatment of life-threatening infections caused by Gram-negative multidrug-resistant bacteria.
Seeding Drug Discovery Development of a small molecule inhibitor of EBNA1 to treat Epstein-Barr Virus (EBV) Latent Infection and Associated Disease Epstein-Barr Virus (EBV) is estimated to be responsible for ~1% of all human cancers worldwide including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, gastric carcinoma, NK/T cell lymphoma, and lymphoproliferative disease in the immunosuppressed.

The World Health Organisation classifies EBV as a type I carcinogen. Maintenance of latent EBV in infected cells depends on the continuous expression of one viral protein, EBNA1. The essential role of EBNA1 in cell proliferation, transformation and lymphomagenesis associated with EBV malignancies makes it an attractive target for drug discovery and development.

Recently, the crystal structure of EBNA1 has been determined and revealed a druggable surface within its DNA binding domain. Exploiting this property, the team of Professor Lieberman at the Wistar Institute in Philadelphia completed a successful high-throughput screening campaign. Supported by a three year Seeding Drug Discovery award the team will now use medicinal chemistry and structure-based drug design methods to optimize promising starting points into small molecule inhibitors of EBNA1. The goal of this project is the development of a pre-clinical candidate ready to be taken into Phase 1 first in human clinical trials. This innovative project has the potential to deliver a completely novel anti-viral in a field of significant unmet medical need.
Seeding Drug Discovery Development of a membrane-targeted antibiotic for complicated skin and skin structure infections caused by multidrug-resistant bacteria The lack of treatments currently available for multi-drug resistant bacteria is one of the most pressing global health issues today. This crisis has been clearly noted by key UK, European and US opinion leaders and government organisations.

Professor Matthew Cooper and his colleagues at the University of Queensland have received a Seeding Drug Discovery award to help to address this problem. The team are using a natural product which has been modified to bind more tightly to bacterial membranes, and not bind to human cell membranes. They plan to develop this modified natural product into a ?best in class? antibiotic for the treatment of infections by bacteria and resistant superbugs.
Seeding Drug Discovery Development of a preclinical drug candidate for treatment of visceral leishmaniasis through optimisation of scaffolds identified from a phenotypic HTS screen of L. donovani axenic amastigote proliferation Leishmaniasis is a widespread parasitic disease with frequent epidemics in the Indian subcontinent, Africa, and Latin America.  The disease is responsible for ~50K of deaths each year, and substantial morbidity.

In its most severe form, visceral leishmaniasis (or kala-azar), the disease is characterized by parasitic invasion of internal organs, and is almost always fatal if left untreated. Several drugs are available but these suffer from multiple shortcomings such as toxicity, failure of treatment due to parasite resistance, and length and cost of treatment. From extensive high throughput screening of compound libraries, a research team led by Dr Richard Glynne at the Genomics Institute of the Novartis Research Foundation have identified several chemical scaffolds that selectively kill Leishmania parasites at concentrations having no effect on human cells. The aim of the project is to optimize these scaffolds towards the identification of an orally available small molecule with efficacy in mouse and hamster models of visceral leishmaniasis. Such a compound would be suitable for toxicity studies in support of clinical testing.
SEEDING DRUG DISCOVERY Identification of PARP inhibitors for cancer therapy While effective treatments for many forms of cancer exist, therapies that are tailored for patients with niche forms of the disease, such as triple negative breast cancer are currently unavailable.

The Trust has awarded £3.9 million over three years to Prof. Alan Ashworth, FRS, Dr. Christopher Lord, Prof. Caroline Springer and Prof. Laurence Pearl, FRS, for the development of orally available small molecules that could target specific cancer subtypes.
Researchers led by Prof Alan Ashworth and Dr Christopher Lord have pioneered the exploitation of novel therapeutic approaches such as synthetic lethality and the use of PARP inhibitors in cancer treatment. PARP (Poly ADP-Ribose Polymerase) enzymes modify proteins and control cell function by catalyzing the addition of poly (ADP-ribose) polymers onto substrates. With funding from the Trust, Ashworth, Lord, Springer and Pearl, in collaboration with Domainex, will develop novel small molecule inhibitors that target additional PARP superfamily members. These inhibitors will be assessed in specific tumour models and then progressed into clinical candidates that could be ultimately assessed in drug trials that target cancer subtypes for which there is significant unmet clinical need.
Fragment-based approaches to the design of candidate drugs that interrupt protein-protein interactions involved in cell regulation
Seeding Drug Discovery The use of fragment-based drug discovery to identify novel drug candidates that modulate the BRCA2-RAD51 interaction for the treatment of cancer The Trust has awarded over £2.4 million to Chris Abell, Tom Blundell, Marko Hyvonen, Grahame McKenzie and Ashok Venkitaraman at the University of Cambridge to use fragment-based approaches to design and make molecules that disrupt the interaction of two important proteins in human cells, the recombinase RAD51 and the product of the breast cancer-associated gene BRCA2.

These proteins are involved in the repair of DNA breakage, and blocking their interaction should result in sensitization of cancer cells to DNA damage, e.g. by radiation, or directly induce cancer cell death during proliferation. Potent compounds will be developed by synergistic use of X-ray crystallography and synthetic organic chemistry, and improved in a highly focused way to make sure they are safe and suitable for development into possible drug candidates. The lead compounds will be tested against different cancer cell lines to identify susceptible cancers, the most probable therapeutic target being lung cancer. This funding follows on directly from a Translation Award to pioneer the use of fragment-based approaches against protein-protein interactions. That project established the use of biophysical methods, especially NMR spectroscopy and X-ray crystallography to identify fragments that bound at specific sites on a protein interface and to iteratively grow these fragments into successively more potent compounds.
A new approach to the treatment of invasive pneumococcal diseases using drugs that inhibit the activity of a pneumococcal virulence factor
Seeding Drug Discovery A new approach to the treatment of invasive pneumococcal diseases Streptococcus pneumoniae causes a very high number of cases of pneumonia, meningitis and bacteraemia, worldwide.  Despite using antibiotics that kill the bacterium, a large number of patients still die and in meningitis, many survivors have profound neurological handicap. This is because the bacterium produces a very damaging virulence factor that is not inhibited by antibiotics.

This problem constitutes an unmet medical need that Professor Peter Andrew and colleagues from the University of Leicester are proposing to fulfill. They have identified that small molecules can inhibit this virulence factor and are effective in vivo. The team have been awarded funding through the Seeding Drug Discovery initiative to identify new small molecules and through a programme of medicinal chemistry, combined with in vitro and in vivo testing, to identify lead compounds with appropriate efficacy, pharmacokinetics and toxicology. The aim is that giving such molecules will reduce the number of patients that die or suffer handicap as a result.
Development of Novel Aminoglycosides for the Treatment of Multi-Drug Resistant Gram-Negative Bacteria, including MRSA and Enterobacteriaceae
Seeding Drug Discovery Novel aminoglycosides for the treatment of multi-drug resistant Gram-negative bacteria Aminoglycosides are a proven class of antibacterials that remain in extensive clinical use despite growing drug resistance.  The Trust has provided a programme-related investment of $8 million (£4.1 m) to San Francisco based Achaogen Inc, to develop novel aminoglycoside compounds to tackle emerging resistance. Achaogen will progress a lead scaffold with activity against Staphylococcus aureus and highly resistant Enterobacteriaceae and a separate chemical series with extended spectrum that also includes multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Both scaffolds will be advanced via in vitro and in vivo efficacy, pharmacokinetic, and safety assays, culminating in the identification of a clinical candidate.
Retinoic acid receptor a agonists for the treatment of Alzheimer's disease
Seeding Drug Discovery Retinoic acid receptor a agonists for the treatment of Alzheimer's disease The current licensed treatments for Alzheimer's disease improve the symptoms that people experience but do not alter the progression of the underlying disease changes in the brain.  Most of the attempts to develop new treatments have focused on altering deposits of the amyloid protein in the brain, but despite more than a decade of intensive research this has still not yielded any new therapies in the clinic.

The studies of Dr Jonathan Corcoran of King's College London highlight a specific retinoic acid receptor (RAR)a agonist as a novel and exciting target for the development of new treatments. This agonist has two mechanisms of action - it regulates amyloid deposits in the brain and also plays a key role in the survival of neurons. In their project they will generate novel RARa agonists for the treatment of Alzheimer's disease.
Selective glucocorticoid receptor agonists for the treatment of inflammatory conditions
Seeding Drug Discovery Selective glucocorticoid receptor agonists for the treatment of inflammatory conditions Research by Professor David Ray and his team at University of Manchester has identified how to modulate the function of the glucocorticoid receptor.  The glucocorticoid receptor responds to both natural hormones and synthetic glucocorticoids to inhibit the inflammatory response. Inflammation lies behind many important human diseases, including rheumatoid arthritis, and opening up novel approaches for therapy offers new hope for these chronic, disabling conditions.

The award will allow development of new molecules capable of harnessing the glucocorticoid receptor for treatment of multiple inflammatory diseases, without the wide range of side effects that currently limit use of conventional drugs. If successful the research will lead to an orally active drug for use in inflammatory arthritis within five years.
Translation Award Phase I dose escalation trial of a group B oncolytic adenovirus (ColoAd1) administered by intrahepatic artery infusion in patients with primary or secondary liver cancer The Wellcome Trust has awarded up to £1.8 million to PsiOxus Therapeutics to support clinical development of a virus that attacks cancer cells. Clinical trials of the virus in patients are expected to begin in early 2012.  Viruses that preferentially attack cancer cells whilst leaving normal tissues unharmed are known as oncolytic viruses. The oncolytic virus ColoAd1 was developed using the evolutionary principle of natural selection to generate a virus with preferred specificity for cancer cells as a possible new therapy for cancer.

Laboratory studies have shown that ColoAd1 has selectivity for killing cancer cells from a wide range of solid tumour types but shows little or no activity on normal tissue. Compared to other oncolytic viruses in development as cancer therapies, ColoAd1 has been shown to retain a high level of activity in human blood. This means that it could potentially be administered systemically as a treatment for cancer that has already spread to other tissues, known as metastatic disease.PsiOxus will use the Translation Award from the Wellcome Trust to conduct a phase I/II clinical trial of ColoAd1 in patients with metastatic colorectal cancer, to determine the safety and tolerability of the virus. Future studies are also planned in patients with other solid tumour types, including primary hepatocellular cancer and ovarian cancer.
Retinoic acid receptor a agonists for the treatment of Alzheimer's disease
Translation Award Development of a multi-peptide immunotherapeutic for Type 1 diabetes to first-in-human stage (MultipPepT1De) Type 1 diabetes (T1D) is an inflammatory disease in which cells making insulin (β-cells) are killed by the immune system. It arises predominantly in childhood, is increasing in incidence and carries significant risk of disease complications and early death, even when patients have repeated daily insulin injections. There is thus an imperative to find well tolerated strategies for treatment and or prevention of T1D.

Professor Mark Peakman at King's College London School of Medicine has been awarded funding to develop a strategy known as peptide immunotherapy. By introducing selected fragments of key proteins from β-cells in a form that switches off inflammation, it is hoped that this therapy will "re-set" the immune system. Peptide immunotherapy is under development in other inflammatory diseases (allergy, multiple sclerosis) using cocktails of peptides, and shows considerable promise, as well as an excellent safety profile and the potential for long-lasting effects.
cGMP Manufacture of T-cells for immunotherapy
Translation Award cGMP Manufacture of T-cells for immunotherapy Gregg Sando, Cellmedica has received translational funding to develop a cGMP procedure to isolate and prepare T-cells for anti-viral therapy.  T-cell immunotherapy has been shown to effectively treat viral infections on patients undergoing immunosuppression therapy, for example following transplant operations. Clinical availability of T-cells has been restricted in part due to regulatory issues. This project sought to address the lack of a cGMP protocol for this approach, using established commercially available laboratory protocols and drawing together several clinical experts from across the UK.
Characterisation of novel molecules with immunosuppressive properties
Translation Award Characterisation of novel molecules with immunosuppressive properties Trino Therapeutics Ltd has received Translation Award support to progress a candidate drug for Inflammatory Bowel Disease through preclinical studies in preparation for a clinical trial.

Trino Therapeutics Ltd is a Campus Company from Trinity College Dublin. The group had previously received Wellcome Trust support to validate its proprietary chemical series in appropriate models of disease.
Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK T:+44 (0)20 7611 8888