Therapeutics

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.

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 Trust funding, Professor Johan Neyts (Rega Institute) together with the Centre for Drug Design and Discovery (CD3) at the University of Leuven (KULeuven) will undertake a programme to identify and develop potent inhibitors of dengue. Such inhibitors may later enter preclinical and clinical development for the prevention as well as the treatment of dengue.

 
Professor Robinson and his team have identified novel, drug-like chemical compounds - Allergy Delivery Inhibitors (ADI) - that combat a root cause of asthma and allergic diseases of the nose, eyes and skin.  The ADIs target allergens excreted by dust mites, tiny creatures that live in the carpets and soft furnishings of homes, offices, trains, planes and cars. The development of ADIs is intended to provide relief to people with an established allergy caused by dust mites and, potentially, to prevent the development of allergic disease in others.  St George’s, University of London is the hub of the programme and will develop a drug for clinical trials in the next few years. The team, which includes Professor David Garrod from the University of Manchester, are working with pharmaceutical research and development contractors worldwide to carry out this groundbreaking work.  Asthma and allergic conditions such as rhinitis, conjunctivitis and dermatitis are an escalating problem expected to affect more than 100 million people globally by 2011. In the UK, 5.2 million adults and 1.1 million children currently receive treatment for asthma, creating a significant social and healthcare burden for the NHS.

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.

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.Dr David Madge from 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.

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, Professor Richard Marais and Dr Janine Erler from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX.They shall apply 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

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?, 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 2 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.

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.

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.

The majority of researchers now think that in Alzheimer's disease a normally occurring brain protein called A? accumulates and sticks to itself, becoming toxic and causing the disease. This aim of this project is to design molecules that block the formation of this toxic form of A?. Senexis Limited, a leading biotechnology company working in the field of ageing-related diseases, has discovered prototype molecules working in this way. With further improvement, these have potential to provide a new treatment for Alzheimer's disease. The company has received investment from the Wellcome Trust's Seeding Drug Discovery initiative to undertake this work, the successful execution of which will provide a candidate molecule for preliminary safety testing and ultimately, full toxicological testing. The proposed research may lead to a new treatment in eight to ten years.

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)? 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 radio-mimetic 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.

This hormone is released during a meal and acts as a neurotransmitter to indicate that a person is full. However PP in its present form is rapidly metabolised by the body. This inaugural award of the Trusts Seeding Drug Discovery initiative plans to develop a synthetic, injectable form of PP that is longer lasting and can be administered to patients on a weekly basis to make it more practical. If successful in suppressing appetite, the proposed research may lead to a treatment to tackle obesity within five to eight years.

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.

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% of new drug approvals. However, 98% 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.

The Trust has awarded over £1 million to Professor Sir Tom Blundell and colleagues at University of Cambridge to identify candidate ligands that may advance cancer therapeutics. The applicants plan to extend fragment-based approaches and design novel candidates that interrupt protein-protein interactions exploiting small pockets in protein-protein interfaces, particularly where one component is a flexible polypeptide that assembles to give a specific structure only in the multiprotein complex. They are specifically examining the multiprotein complex of human recombinase, Rad51, and the product of the breast cancer-associated gene, BRCA2. The applicants plan to screen using X-ray, NMR, mass spectrometry and other biophysical approaches, together with biochemical and biological assays, to select and validate useful ligands. This project could identify drugs that block the BRCA2-RAD51 interaction to sensitise cancer cells to radiation, DNA cross-linking agents or replication inhibitors, or to directly induce cancer cell death during proliferation. In addition, this project has the potential to validate that protein-protein interactions are potentially druggable.

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.

Pharmatrin 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?, promotes the clearance of bacteria from the site of infection. The group have received support to progress the chimeric protein through formal preclinical evaluation.