Therapeutics

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.

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.

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.

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.

 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.
 

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.

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 Haigh¹s team at Queen¹s 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.

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.

Bariatric surgery is effective, but is expensive, inflexible and carries a significant mortality rate. There is therefore an unmet need for new medical treatments. Gut and pancreatic hormones, secreted post-prandially, naturally reduce appetite via feedback mechanisms. These hormones are therefore promising anti-obesity drug development targets.

Professor Sir Steve Bloom, Imperial College and his team have developed a degradation resistant peptide analogue of the hormone pancreatic polypeptide called PP 1420 that is a specific agonist of the neuropeptide Y subtype 4 (Y4) receptor, with the following features:
• administered subcutaneously as a treatment for obesity.
• composed of all natural amino acids, without modifications
• capable of reducing food intake and body weight when given to animal models of obesity
• appeared free of side effects.
Funded by a Wellcome Trust Seeding Drug Discovery Award, the team has developed PP 1420 from pre-clinical to a Phase 1 first time in man study.  PP 1420 was found to be well-tolerated and not significantly toxic in statutory pre-clinical studies in two species. A GLP-compliant assay in a human plasma matrix for PP 1420, based on LC/MS-MS, was developed.
 
• A Phase 1 study was conducted by the research team in the Sir John McMichael Centre at Hammersmith Hospital. When administered to healthy human volunteers at doses ranging from 2-8 mg in this study:
• No adverse effects were seen.
• No evidence of peptide immunogenicity.
• Maximal plasma concentrations were seen at approximately 1 hour after subcutaneous injection.
• The terminal elimination half-life was estimated at approximately 2.5 hours.
• Systemic exposure (AUC0-8 and Cmax) was proportional to the dose.

The findings from this study have been published in Tan et al. (2011) Br J Clin Pharmacol (doi:10.1111/j.1365-2125.2011.04082.x)

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.

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.

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.

 
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.

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

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.

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 Technology Transfer is seeking a development and commercialisation partner for this programme.
Watch a short video in which the researchers explain their work 

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.

The infection now accounts for over three times as many deaths in the UK than infections due to MRSA. In the UK alone there were over 36 000 cases reported in the year ending March 2009 and several thousand deaths. Antibiotics for CDI are limited, of sub-optimal efficacy and are associated with around a 30 per cent relapse rate with each period of relapse invariably resulting in more severe forms of the disease.   Summit plc is developing novel, highly specific antibiotics for CDI with SMT19969, the lead compound from the programme, currently in late stage preclinical development.  SMT19969’s highly selective killing of C. difficile, without affecting the normal healthy gut bacteria, is expected to result in a significant healthcare benefit by reducing rates of relapse which remains the central clinical issue in CDI management.The programme is being funded by the Seeding Drug Discovery Initiative which has enabled Summit to accelerate the development of SMT19969 as a much needed therapy for a life threatening infection.

The majority of researchers now concur that a normally occurring brain protein called Ab misfolds to become synaptotoxic and thus underlies the chronic synaptic loss that defines Alzheimer?s disease. This project has successfully discovered orally bioavailable and brain-penetrant molecules that block the formation of this toxic form of Ab and preserve normal synaptic function.  Furthermore, SEN1500 was the first of these molecules to increase the clearance of Ab from the brains of transgenic mice. Senexis Limited, a leading biotechnology company working in the field of ageing-related diseases, is now developing SEN1576, which has the potential to provide a new disease-modifying treatment for Alzheimer's disease. The company received investment from the Wellcome Trust's Seeding Drug Discovery initiative to complete the discovery of SEN1576, which has completed preliminary safety testing and is now being prepared for further toxicological testing. SEN1576 may enter initial clinical trials in about a year from now.

Dr Jillian Baker, Professor Steve Hill, Dr Barrie Kellam and Professor Peter Fischer at the University of Nottingham have been awarded funding to develop highly selective beta-1 antagonists. The programme is based around a lead compound with over 3000-fold beta-1 selectivity and demonstrated activity in an in vivo animal model. Once developed, the group's drug candidate will by definition have less respiratory side-effects and should be able to be given safely to the hundreds of thousands of patients with both heart and lung diseases.

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.

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.

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.

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.

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.

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.

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.

Over the past few years the prevalence of invasive MRSA has significantly increased worldwide including the UK and continental Europe and the US, where it is now estimated to cause more deaths than HIV. This is now a very serious and growing public health issue that needs to be addressed. The GSK-Wellcome Trust research program will build on both the extensive GSK knowledge of structure-activity relationships for this novel class of antibacterial molecules, and the considerable learnings from advanced studies on previous compounds from this series. GSK's expertise in this area, coupled with the promise of new SAR from an innovative medicinal chemistry strategy, gives a high probability of success on delivering a much-needed novel MRSA drug candidate.

The Trust has provided £2 million programme related investment to Cambridge based Astex Therapeutics to use their proprietary fragment-based screening approach, Pyramid (TM), to identify and develop novel inhibitors which bind to newly identified regulatory site on a HCV viral protein. Such novel agents would be of significant value in a disease where combination therapy is vital to limiting the emergence of viral resistance.

The award will fund a multidisciplinary team of medicinal and in silico chemists, pharmacologists and molecular parasitologists for two years.The project aims to develop inhibitors to candidate selection against a novel component of the parasite's electron transport chain.

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.

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.

A dramatic fall in blood pressure (hypotension) in septic patients contributes to death. Current strategies to block this hypotension are only partially effective and carry side effects that might reduce patient survival. One of the mechanisms that causes hypotension is the over production of a molecule, nitric oxide (NO), which causes blood vessels to dilate. A multidisciplinary collaboration of scientists, lead by Professor James Leiper, from the departments of Medicine and Chemistry at University College London together with structural biologists from Birkbeck College have identified a novel mechanism to block hypotension in sepsis. This approach works by increasing the level of a naturally occurring compound (asymmetric dimethylarginine, ADMA), which inhibits NO production. This project aims to identify and characterise small drug-like molecules that increase the level of ADMA and will therefore have therapeutic utility in the treatment of sepsis. The research team is uniquely placed and propose to test their candidate molecules for safety in healthy humans in the third year.

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.

Pentraxin Ltd, a spin-out from University College London and headed by Professor Mark Pepys has been awarded funds to construct compounds targeting plasma transthyretin, which could be used as drugs for treating and preventing acquired and hereditary human systemic transthyretin amyloidosis. The aim is to optimise the design, synthesis, and properties of a transthyretin targeting drug and complete the comprehensive safety and efficacy evaluation required prior to administration of a validated candidate compound in humans.

Sentinel Oncology, a drug discovery company focused on developing next drugs for cancer, and Professor Ashok Venkitaraman, University of Cambridge have collaborated to develop a new technology, Targeted Synergy, which is designed to overcome the twin problems of toxicity and drug resistance in cancer chemotherapy. The majority of cancer patients receive treatment with radiation or radiomimetic drugs, but cancer cells are often resistant to these agents, and they cause toxic side effects. Targeted Synergy works by combining two synergistic effects in a single molecule that is activated selectively in cancer cells to help overcome resistance and kill them with less general toxicity to the patient. The principles behind Targeted Synergy incorporate Professor Ventikaraman's research, which have been exploited by the Sentinel Oncology team to create several new classes of drugs that work in this way. Sentinel's Targeted Synergy drugs are expected to be particularly useful in the treatment of brain tumours, for which an effective treatment is not currently available.

GlaxoSmithKline (GSK) has received a £4 million award to accelerate development of compounds for the treatment of Gram-negative bacteria, which are becoming increasingly resistant to multiple antibacterials. The research will target Gram-negative bacteria, such as Pseudomonas, Klebsiella and Acinetobacter, which are increasingly resistant to available antibacterials and commonly cause hospital-acquired pneumonia and septic shock, particularly in patients in intensive care units. Without adequate therapy, patients often confront a poor prognosis - mortality is high, and recovery, when it occurs, can be long and complicated. Virtually no novel-mechanism antibacterials are in development to address this rising need. Gram-negative bacteria are particularly difficult to attack as they have an outer membrane surrounding the bacterial cell wall, which interferes with drug penetration. New medicines must not only be toxic to the pathogen, but must first overcome the barriers to entry into the cell.

The emergence of MRSA in particular has received considerable media attention and is attributed to more than 1400 of the deaths caused by infection and complicates the treatment of over 7000 patients in UK hospitals per year. With the aid of Trust funding, Prolysis will progress one of their novel antibacterial chemical series that specifically inhibits Staphylococcal cell division through a chemical optimisation programme, preclinical development and into Phase I clinical trials. The project aims to deliver a new, targeted therapy for the treatment of Staphylococcal infections acquired in hospitals or the community and to offer a prophylactic treatment for MRSA carriers prior to invasive procedures.

HIV/AIDS is being brought under control in wealthy countries, but more than 2 million new infections occur per year in the developing world, more than 95 per cent of the global total. Women and girls are often unable to negotiate any form of protection for themselves, and thus are particularly at risk. In Africa south of the Sahara 75 per cent of all young people infected are female.  There will be no effective vaccine for years and many hopes rest on 'microbicides', substances that could be applied to the vagina before sex and that would prevent infection. At present, a microbicide effective against HIV is not available: such a substance would greatly empower women and girls to protect themselves and their partners by a method under their control. 5P12-RANTES is an extremely potent anti-HIV substance, suffers very little from the common problem of generating drug-resistant strains, can be produced cheaply by fermentation in yeast and is highly resistant to tropical temperatures. Mintaka will use the funds granted to develop and execute a larger scale preparation method to cGMP standards, study stability and formulation, and execute some remaining animal toxicity tests that are required before 5P12-RANTES can be used in humans.

PT1.2 is based on a new class of antibacterial proteins called SASPs, which bind to bacterial DNA resulting in rapid speed of kill. Phico Therapeutics envisages developing a fast-acting, easily applicable nasal gel which would combat both hospital and community MRSA transmission and drug-resistance. There is an urgent need to develop innovative ways to manage the transmission of antibiotic-resistant bacteria in the hospital and care-home environments and if successful, this technology may provide an important new tool in the fight against MRSA and other pathogenic bacteria.

The Wellcome Trust, the Singapore Economic Development Board and the Medicines for Malaria Venture (MMV) have pledged over £10 million in funding, while the Novartis Institute for Tropical Diseases (NITD) will manage the programme and conduct research jointly with several institutions, including the Genomics Institute of the Novartis Research Foundation and the Swiss Tropical Institute. One of the top three killer diseases in tropical countries, malaria is estimated to kill over one million people and affect around 300-500 million people annually. Research at Singapore-based NITD will focus on the development of a one-dose cure for Plasmodium falciparum, the most dangerous form of malaria, and a new way to cure Plasmodium vivax, the most frequent and widely distributed cause of malaria.

The grant - awarded to Professor Mike Ferguson, Professor Alan Fairlamb, Professor Bill Hunter, Professor Ian Gilbert, Professor Julie Frearson and Dr Daan van Aalten - will fund pre-clinical drug discovery with an initial focus on Human African Trypanosomiasis. This disease kills 50 000 people per year, and current treatments are inadequate. The £8.1m grant will allow the University to add a team of 16 scientists to all the disciplines needed from those of biology to drug design, synthesis and testing. The new activities will be housed in the newly completed Centre for Interdisciplinary Research and co-funded by The University of Dundee, the Scottish Higher-Education Funding Council and by The Wolfson Foundation.

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.

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 ?-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

Vaccines have their problems as they act only against the current viruses and are ineffective against new pandemic strains. The antivirals Tamiflu and Relenza act against all flu viruses, but there is already widespread resistance to Tamiflu. New measures are urgently needed. Professor Nicholas Dimmock's approach, at Warwick University, has been to isolate a natural 'protecting virus' called FluPro®. This is a harmless version of the flu virus itself and is delivered to the nose. Only those cells that influenza normally infects get treated.  FluPro has been tested in laboratory models where a single intranasal dose completely prevents disease caused by several different flu viruses. Post-infection treatment is also effective. FluPro tricks infectious flu viruses into making non-functional virus particles (i.e. more FluPro) instead of the infectious virus. In this way it reduces the infection and the spread of infection, and increases the amount of protection.

Human growth hormone is a large (22 kDa) protein drug used to treat growth disorders in children and adults. Biological drugs such as growth hormone are an increasingly important class of therapeutics and represent over 30 per cent of new drug approvals. However, 98 per cent of biological drugs are administered by frequent injection which is strongly disliked by patients and their carers. This can lead to poor patient compliance and sub-optimal clinical outcomes. Success in this project will see the development of the first nasal spray of a large biological drug and demonstrate the proof of principle of the CriticalSorb technology in humans. The CriticalSorb technology has the potential to enable the delivery of a wide range of biological drugs via nasal spray as an attractive alternative to injection.

These drugs deactivate cytotoxic T cells and affect their ability to fight infections. Epstein-Barr virus (EBV) is a common persistent infection controlled by cytotoxic T cells in healthy people, but can cause post transplant lymphoproliferative disease (PTLD), which is often fatal. Previously a bank of 100 cytotoxic T cell lines (CTL) grown from healthy blood donors and used these to treat PTLD. A phase II clinical trial used these allogeneic EBV-specific CTL grown from healthy blood donors on a best HLA match basis and showed a 52 per cent response rate at six months in PTLD patients unresponsive to all other conventional therapies. This treatment is now ready for transfer to the clinic. However, the 100 EBV specific CTL lines developed for this proof of principle trial were grown from the peripheral blood of healthy Scottish blood donors under good laboratory practice, but these conditions did not comply with the subsequent 2004 EU Directive on Tissues and Cells and requirements for HTA or MHRA licensure.

Hence most anticancer drugs cannot access the brain in high enough quantities to kill the tumours, without producing therapy-limiting side effects. Additionally some patients have inoperable tumours and would benefit from improved drug treatments. Professor Ijeoma Uchegbu, School of Pharmacy at the University of London, has developed nanotechnology that significantly increases the potency of drugs in the brain; this project will build on earlier research by demonstrating that the nanotechnology formulation can result in significant anti-tumour activity while sparing the healthy brain and bone marrow.

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 seeks 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.

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.

This mechanism, termed Resolution Therapeutics (TM), promotes the clearance of bacteria from the site of infection. The group have received support to progress the chimeric protein through formal preclinical evaluation.