Popular Charity, Public and Private Sector Collaborate to Fight Genetic Disorders

Généthon and Polyplus-transfection team up to contribute to researching gene therapies for Duchenne Muscular Dystrophy

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There is often a strange contradiction between advances of the diagnosis and treatment of serious diseases and the understanding of their cause. For example, advances in breast cancer have led to significantly improved survival rates, while the causes are still not fully understood. However, there has been relatively little progress in developing and commercializing broad and effective therapies for genetic disorders, such as Duchenne Muscular Dystrophy (DMD), affecting around 1 in 3,600 boys. Yet the cause of DMD is well understood.

DMD is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. The physical effects of DMD are progressive and severe. Starting with early age muscle weakness, patients are usually wheelchair bound by age 12 with progressive muscle deterioration and loss of movement leading to paralysis. Average life expectancy is around 25 years. Currently there is no cure for DMD.

Modern DNA testing provides improved confirmatory diagnostics, and the conditional European approval of PTC Bio’s DMD therapy Translarna™ in July fuels hopes for a break through therapy. The quality of life and life expectancy of many DMD patients is being improved by use of a combination of physical therapy and drugs such as corticosteroids and beta2-agonists. However, the impact of the disease on the patient and their families is simply devastating.

The dream of an effective gene therapy is to treat diseases by transfer of “good” genetic material into a patient to complement or to create a sustained correction in aberrant gene expression, such as with dystrophin in DMD. The gene therapy concept, developed in the 1950s was inspired by major contemporary discoveries in basic genetic research. The 1980’s saw further development with the start of first gene therapy clinical trials.

The virus-mediated gene therapy clinical trial for X-linked severe combined Immune deficiency was conducted in 2000 (by Drs M. Cavazzana-Calvo and A.Fisher from the Hôpital Necker in Paris, France) was an essential development. While the trial resulted in effective and life-saving immune reconstitution in 10 out of 11 patients, it also revealed the serious risks associated with virus-mediated gene therapy delivery, including the onset of Leukemia.

The first ever approved gene therapy treatment was commercially released in China in 2003. Gendicine is an adenovirus-based vector (AAV) expressing the p53 gene. It is injected into the patient’s peritoneum for the treatment of head and neck squamous cancer (HNSC). The first gene therapy treatment to be granted market authorization in Europe was Glybera® in 2012. Glybera compensates for lipoprotein lipase (LPL) deficiency, a disease preventing the metabolism of fats in the blood and resulting in severe pancreatitis. Glybera is a virus which carries the functional LPL gene which upon intramuscular injection restores fat breakdown in the blood, preventing life threatening recurring pancreatic attacks.

Other accomplishments in the field of gene therapy include a successful stem cell therapy for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID), a therapy for adrenoleukodystrophy (ALD), a therapy for β-thalassemia, therapies against the Wiskott-Aldrich syndrome (WAS) and the chronic granulomatous disease (CGD).

There has been a massive resurgence in venture interest and access to IPO funding in the last two years for gene therapy companies. Total funding between January 2013 and April 2014 reached $618 million. Companies like BlueBird Bio raised $116 million in June this year via an IPO. Spark Therapeutics raised $50 million in October 2013. Both are focused on other important genetic disorders such as Childhood Cerebral ALD and Genetic Blindness rather than DMD.

Proactive steps and messages by the regulatory bodies like the U.S. Food and Drug Administration (FDA) have encouraged companies active in DMD drug development like Sarepta Therapeutics and Prosensa to accelerate development and drive their clinical programs forward. The European Medicines Agency (EMA) supported PTC Bio in the development and limited commercial release of their DMD therapy. GSK and Shire, currently being acquired by Abbvie, are active in gene therapy projects. However, Big Pharma has yet to put their resources behind the search for a DMD cure.

So it falls to organizations like AFM-Telethon (Association Françaisecontre les Myopathies), a French fund-raising event, to provide leadership in research funding, and support for DMD patients and their families. The AFM-Telethon, which takes place on the first weekend of December each year with the help of hundreds of thousands of volunteers, millions of participants and lots of well known popular personalities, generates both awareness and cash. The Telethon fund raising format was imported from the US in 1986 by Pierre Birambeau, whose son Damien suffered from DMD. The first AFM-Telethon raised around $37.6 million in today’s money and is now a 30-hour TV show. In 2013, it raised more than €80 million.

One of the organizations part funded by the AFM-Telethon is Généthon, a non-profit biotherapy R&D organization based near Paris, with a mission to design gene therapy products for rare diseases, ensuring their pre-clinical and clinical development and production in order to provide patients with access to these innovative treatments. Généthon, as an integrated R&D center, ensures translational development from research to clinical validation, including bio-manufacturing.

More than 230 people work at Généthon. 80 percent are specialists in biotherapies and clinical development: researchers, Pharm. Ds, MDs, PhDs, experts in quality control and regulatory affairs and engineers. There are more than 10,000 m2 of laboratories housing a unique in vitro and in vivo therapeutic testing platform at their Evry site. This incorporates; a functional evaluation platform (including ultrasound testing); an imaging-cytometry platform (confocal, macroconfocal and biophotonic microscopes); multiple molecular and physio-pathological systems for the examination of isolated living cells as well as a modern histology department.

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