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Theme 1: Advancing Genetic Discoveries Into Clinical Practice

The first thematic call focused on projects aimed at bridging the gap between the current understanding of genetic variation on disease susceptibility (basic knowledge) and clinical practice.

 

Theme 1 Projects:

 

Development and application of a targeted array test to diagnose and direct therapy in haematological cancers
Development and application of a targeted array test to diagnose and direct therapy in haematological cancers
Topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours

View Abstract

Leukaemia is a form of cancer that affects blood cells and arises in the bone marrow or lymphoid organs. There are several types of leukaemia, depending on which blood cells are affected.

Although several treatments are available, the current genetic tests used to guide therapy are not sufficiently precise. This means that some patients suffering from leukaemia may not respond to treatment or may suffer adverse side-effects. In order to be most effective, treatment must be tailored to the individual. This is also important when considering emerging therapies that are extremely expensive and must be used judiciously.

We have developed specialized approaches that use microarray technology to test, in detail, the genetic make-up of blood cells from patients with B-cell chronic lymphocytic leukaemia.  During our three year HIC Fund study, these approaches will be validated and adapted specifically for use in a clinical setting.

The more precise detection of relevant genetic alterations will enable doctors to provide the most suitable treatment for patients, minimizing side-effects of treatment, reducing mortality and NHS care costs. The approach will be suitable for use in hospital laboratories worldwide.

Gene therapy for blindness caused by choroideraemia a Phase I clinical trial
Gene therapy for blindness caused by choroideraemia a Phase I clinical trial
Principal Investigator:  Professor Robert MacLaren
Organisation: University of Oxford
Start Date 1st February 2011
End Date: 31st January 2015

View Abstract

We are undertaking a clinical trial using gene therapy to treat a disease that causes blindness known as choroideraemia. This condition is currently incurable and affects thousands of people worldwide. The principle of gene therapy is to use the shell of a virus (known as a vector) to carry a segment of DNA into the cells of affected patients where it can have a beneficial effect. In the case of choroideraemia there is deficiency of a gene known as REP1. We have put this gene into a viral vector and shown in our laboratory that it can correct the choroideraemia defect. We have now reached the point where we are ready to assess the potential benefit of this treatment in patients. We have designed a study involving 12 patients across four NHS sites that would represent the world's first ever clinical trial for this disease. We will assess the effects of the gene therapy two years after treating each patient and if it is shown to be successful we will set up regionally located follow-on studies.

Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy
Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy
Principal Investigators:  Dr Matthew Wood, Professor Francesco Muntoni
Organisation: University of Oxford
Start Date 1st March 2011
End Date: 31st December 2017

View Abstract

Duchenne muscular dystrophy (DMD) is the most common lethal variant of muscular dystrophy, and affects 1 in every 3500 live male births or 250,000 people world-wide. Recent encouraging clinical trials have used antisense oligonucleotides (AOs) which, like “molecular velcros”, are able to temporarily repair the mutated DMD gene and restore the lost dystrophin protein to the muscles of DMD patients. However this approach requires repeated administration of the AO drug in order to achieve some repair of the gene in the skeletal muscle; in addition the heart muscle cannot be targeted efficiently with the current AO chemistries. New generation AOs, never tried before in the human, are able to dramatically improve skeletal and cardiac muscle uptake of these molecules in animal models of DMD and significantly improve their therapeutic efficacy. In this study the MDEX Consortium, a world-leading group of preclinical scientists and clinicians based in the UK developing state-of-the-art therapies for neuromuscular disease plans to focus on the development and optimisation of a safe new generation AO drug which we intend to administer to a group of 9 patients affected by DMD after appropriate safety studies.

Using pharmacogenetics to improve treatment in young-onset diabetes
Using pharmacogenetics to improve treatment in young-onset diabetes (UNITED)
Principal Investigator:  Professor Andrew Hattersley
Organisation: University of Exeter
Start Date 1st October 2010
End Date: 30th September 2013

View Abstract

Monogenic diabetes is an unusual form of diabetes. It usually presents in patients under the age of 30, so is often misdiagnosed as Type 1 diabetes which is more common. Patients with monogenic diabetes can often be treated with tablets rather than insulin injections, leading to better control of their diabetes, and fewer side-effects and complications. Less than 5% of people with monogenic diabetes in the UK have been identified, meaning up to 20,000 patients may still be misdiagnosed and receiving inappropriate treatment.

The aim of the UNITED Project is to identify the prevalence of patients with monogenic diabetes resulting from mutations in the HNF1A, HNF4A, or GCK genes, amongst patients with early-onset diabetes, diagnosed less than 30 years. We aim to develop a health economic model of a care pathway leading to the testing of monogenic diabetes. This will help to identify the best way of ensuring that people diagnosed with diabetes under the age of 30 have all the necessary tests to ensure they have the correct treatment for their particular type of diabetes. A small number of people may, as part of this study, be found to have a specific genetic cause of their diabetes and, in these cases, we will measure the success and benefits of changing their treatment, usually from insulin to sulphonylurea tablets.

Deciphering developmental disorders
Deciphering developmental disorders
Principal Investigator:  Dr Matt Hurles
Organisation: Wellcome Trust Sanger Institute
Start Date 1st October 2010
End Date: 31st March 2017

View Abstract

Thousands of babies are born each year in the UK who fail to develop normally because of errors in their genetic makeup. Currently, diagnosis is restricted to a small minority of children and requires the clinician to recognise the appearance of the child and the pattern of symptoms, supplemented by the use of microscopes to identify large rearrangements of the genetic material in chromosomes. Research shows that the latest molecular testing methods identify previously undetectable changes in chromosomes allowing new diagnoses to be made. However, clinical use is hampered by the limited availability and inconsistent application of these technologies, and by lack of basic knowledge to link genetic changes directly to symptoms. The consequence is that clinical diagnoses remain impossible except for a small number of children.

We propose to apply state of the art molecular testing to 12,000 UK children with abnormal development. The results will provide a unique, on-line catalogue of genetic changes linked to symptoms that will enable clinicians to diagnose developmental disorders. Furthermore, we will design more efficient and cheaper diagnostic assays for relevant genetic testing to be offered to all such patients in the UK and so transform clinical practice for children with abnormal development.

Quantifying disease burden in patients with cancer using tumour-specific genomic rearrangements
Quantifying disease burden in patients with cancer using tumour-specific genomic rearrangements
Principal Investigator:  Dr Peter Campbell
Organisation: Wellcome Trust Sanger Institute
Start Date 1st October 2010
End Date: 1st October 2016

View Abstract

Cancer is caused by the accumulation of genetic damage (mutations) in cells within a particular organ. These mutations are only found in the cancerous cells, and therefore could be used to track the malignancy during treatment. Advances in DNA sequencing allow the high-throughput identification of these mutations from any cancer sample in a clinically relevant time-frame. As tumour cells die, they release their DNA into the bloodstream. We propose to use the new generation of genetic sequencing technologies to identify a particular class of mutations caused by the abnormal rearrangement of chromosomes in patients with breast cancer and colorectal cancer. From these rearrangements, we will develop assays to detect DNA from each patient’s cancer that has been released into the bloodstream. Such assays will be highly specific (minimal risk of falsely positive results) and sensitive (capable of detecting one copy of tumour DNA in many millilitres of blood). We will measure the amount of disease using blood samples collected before surgery, after surgery, during chemotherapy and at regular time-points post-therapy. We will therefore be able to assess the ability of this approach to identify high-risk patients before treatment begins, to monitor response to treatment and to predict cancer relapse before it is clinically apparent.