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5.6.13 Pre-Clinical Gene Replacement Therapy For X-Linked Myotubular Myopathy

The Myotubular Trust is delighted to announce our 2013 research grant to Dr Anna Buj Bello, at the world-renowned not-for-profit orphan disease laboratory, Genethon, in Paris, France.

Our grant will allow Dr Buj Bello to carry out the vital next steps on the road to clinical trials.

Up to now Dr Buj Bello’s work, and her work in conjunction with the University of Washington on XLMTM dogs, has proven the concept of using a virus as a vector to carry the gene into muscle cells. This has brought about a marked improvement in muscle function.

With Myotubular Trust funding, Dr Buj Bello and her team at Genethon will carry out three crucial objectives in order to bring this gene therapy through the pre-clinical phase:

1) Novel Vectors with increased skeletal muscle specificity: Ensuring that the ‘vector’ carrying the gene therapy is the most appropriate way to ‘get into’ muscle cells is a very important next step in preparing for clinical trials. It is vital before we are ever at a point to introduce this into humans, to improve this viral vector so that it expresses myotubularin in muscles rather than in other tissues in the body. It is not known what complications or toxicity could be brought about by too much myotubularin in other bodily tissues, and Dr Buj Bello and her team are uniquely placed to develop an improved and more targeted viral vector for muscle cells specifically.

2) Defining dosage and route of drug administration: Establishing the ideal dosages and best routes of drug administration is also vital at the pre-clinical trial phase of research. This work will be carried out in conjunction with Professor Martin Childers at the University of Washington where they are carrying out experiments on Labrador Retrievers who have a naturally occurring canine version of XLMTM. Dr Buj Bello’s team at Genethon will be responsible for providing the vectors for all of these experiments, and for the in-depth analysis of all animal tissues and bloods in both the dogs in Washington and the mice at Genethon. This analysis is vital to identify how the vector is distributed and expressed through the body, and will help to define dosages. Dr Buj Bello’s team will be responsible for evaluating the immune response of this gene therapy before it is considered safe to bring to human trials.

3) Human vector for clinical trials: The ultimate result of Dr Buj Bello’s grant will be the design, production and assessment of the human vector that will be used in clinical trials in patients with XLMTM. Genethon have unique experience in this field, as they have already developed a human AAV vector for Duchenne Muscular Dystrophy.

Dr Buj Bello’s grant is for £110,000 over two years, and the Myotubular Trust are very grateful to the families and friends of so many of those affected by myotubular and centronuclear myopathy, who have ensured that we are in the position of being able to fund this ground breaking pre-clinical gene replacement therapy for myotubular myopathy. Thank you.

Dr Buj Bello
Dr Buj Bello has been working in the field of myotubular myopathy since 1997. She began this work in the laboratory of Professor Jean-Louis Mandel in Illkirch (Strasbourg), France, where in 1996 the MTM1 gene was discovered. Dr Buj Bello generated the first ever mouse models of myotubular myopathy – a critical step on the road to finding a cure for this condition. She was the first scientist to demonstrate that gene transfer of myotubular myopathy created a ‘striking rescue’ of affected muscles, and prolonged life in mice, and now more recently in larger mammals in her work in collaboration with Professor Martin Childers at the University of Washington working on XLMTM Labrador Retrievers.

Dr Buj Bello’s many years of work on gene therapy is the fundamental foundation stone of the pre-clinical gene replacement therapy now being proposed for myotubular myopathy. She is remarkable in her collaborative approach to her research in myotubular myopathy, and has an impressive track record of international co-operation with other researchers. This approach to sharing learning is particularly important to the Myotubular Trust’s decisions to make research grants.

Genethon, located at Every, France, is a non-profit organisation dedicated to biotherapies for orphan genetic diseases. Genethon has unique experience in the international research community in gene therapy and muscle disorders, and already has several clinical trials on the way for muscle, blood and eye diseases. Genethon has one of the largest viral vector production facilities in the world and has unique expertise to assess the quality and effectiveness of viral vectors for clinical application.

How the Myotubular Trust makes its grants
From inception it has been very important to the Myotubular Trust to ensure that all the funds raised for us are only spent on world-class research. To that end we are very fortunate to have in place a Scientific Advisory Board of eminent scientists in the relevant fields from which a cure for myotubular myopathy is likely to emerge.

The Scientific Advisory Board review all grant applications for us every year, and with their advice, all applications are sent for peer review to the most internationally regarded scientists with renown in the fields of the specific science being proposed in the application. The peer reviewers’ feedback on the proposed project approach, and their up to date knowledge of developments in that field, form a vital part of our decision to fund, but also provide excellent insight and advice to all applicants, whether successful or not.

Read a more detailed description of how the Myotubular Trust funds research.