Microdystrophin restores muscle strength in Duchenne muscular dystrophy

July 25, 2017

Researchers from Genethon, the AFM-Telethon laboratory, Inserm (UMR) and the Royal Holloway University of London demonstrated the efficacy of an innovative gene therapy in the treatment of Duchenne muscular dystrophy. Indeed, after injecting microdystrophin (a "shortened" version of the dystrophin gene) via a drug vector, the researchers managed to restore muscle strength and stabilise the clinical symptoms in dogs naturally affected by Duchenne muscular dystrophy. A first. This work, published today in Nature Communications, has been achieved thanks to donations from the French Telethon.

Duchenne muscular dystrophy is a rare progressive genetic disorder involving all the muscles of the body, and affects 1 in 5,000 boys. It is the most common neuromuscular disorder in children. It is associated with abnormalities in the DMD gene, which encodes dystrophin, a protein that is essential for proper muscle function. This gene is one of the largest in our genome (2.3 million , of which over 11,000 are coding). Because of this size, it is technically impossible to insert the entire DNA for dystrophin into a (or even the 11,000 coding base pairs alone), as is usually done for gene therapy.

To meet this challenge, teams at Genethon developed, in collaboration with a team at Royal Holloway University of London led by Pr. Dickson, and produced, a gene therapy drug combining an AAV-type viral vector with a shortened version of the dystrophin gene (approximately 4,000 base pairs), allowing the production of a functional protein. Dr Le Guiner's team tested this innovative in 12 dogs naturally affected by Duchenne muscular dystrophy. By injecting this microdystrophin intravenously, and hence into the whole body of the dogs, the researchers observed that dystrophin expression returned to a high level, and was significantly restored, with stabilisation of the clinical symptoms observed for over 2 years following injection of the drug (see video). No was administered beforehand, and no side-effects were observed.

Some Golden Retrievers develop Duchenne muscular dystrophy naturally. The successful treatment of these dogs, which show the same clinical symptoms as children with this disease, and are of a similar weight, is a decisive step toward developing the same treatment in children."This preclinical study demonstrates the safety and efficacy of microdystrophin, and makes it possible to consider developing a clinical trial in patients. Indeed, this is the first time that it has been possible to treat the whole body of a large-sized animal with this protein. Moreover, this innovative approach allows treatment of all patients with Duchenne muscular dystrophy, regardless of the genetic mutation responsible," says Caroline Le Guiner, the main author of this study.

"This is tremendously exciting progress towards a gene therapy for DMD. The studies in GRMD dogs have been spectacular and exceeded our expectations. My team has worked for many years to optimise a gene therapy medicine for DMD, and now the quite outstanding work of colleagues in France, in Genethon, in Nantes and in Paris has taken us close to clinical trials in DMD patients. I pay thanks also to the amazing and steadfast support of this research by AFM-Telethon and MDUK (Muscular Dystrophy UK) which has been essential to this achievement." commented George Dickson.

For Frederic Revah, Chief Executive Officer of Genethon: "For the first time, researchers obtained a systemic therapeutic effect on a neuromuscular disease in dogs using microdystrophin, and without immunosuppressive treatment. This highly complex cutting edge technology has been developed as part of an exceptional collaborative effort between Genethon and academic teams from Britain and France. Now our bioproduction experts have the task of producing a sufficient quantity of these new drug vectors, under GMP conditions, for the clinical trial."

"This new evidence of the efficacy of in Duchenne muscular dystrophy strengthens the therapeutic arsenal developed (exon skipping, CRISPR Cas-9, pharmacogenetics, etc.), and the first results are there. We need to forge ahead to complete the final phase and transform these scientific advances into drugs for children," emphasises Serge Braun, Scientific Director of AFM-Telethon.

Explore further: Gene therapy treats all muscles in the body in muscular dystrophy dogs

More information: Caroline Le Guiner et al, Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy, Nature Communications (2017). DOI: 10.1038/ncomms16105

Related Stories

Gene therapy treats all muscles in the body in muscular dystrophy dogs

October 22, 2015
Muscular dystrophy, which affects approximately 250,000 people in the U.S., occurs when damaged muscle tissue is replaced with fibrous, fatty or bony tissue and loses function. For years, scientists have searched for a way ...

Gene-editing alternative corrects Duchenne muscular dystrophy

April 12, 2017
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

New research increases understanding of Duchenne muscular dystrophy

October 13, 2016
A new paper, co-written by faculty at Binghamton University, State University of New York, increases the understanding of Duchenne muscular dystrophy (DMD)—one of the most common lethal genetic disorders—and points to ...

Emflaza approved for duchenne muscular dystrophy

February 9, 2017
(HealthDay) —Emflaza (deflazacort) has been approved by the U.S. Food and Drug Administration to treat Duchenne muscular dystrophy in people five years and older, the agency said Thursday in a news release.

A quantum leap in gene therapy of Duchenne muscular dystrophy

January 15, 2013
Usually, results from a new study help scientists inch their way toward an answer whether they are battling a health problem or are on the verge of a technological breakthrough. Once in a while, those results give them a ...

Often the villain, fructose may play hero's role in muscular dystrophy treatment

March 3, 2017
A substance widely known as a villain for its role in causing obesity-related health problems has emerged as a possible hero in the fight against a debilitating genetic disorder.

Recommended for you

'Human chronobiome' study informs timing of drug delivery, precision medicine approaches

December 13, 2017
Symptoms and efficacy of medications—and indeed, many aspects of the human body itself—vary by time of day. Physicians tell patients to take their statins at bedtime because the related liver enzymes are more active during ...

Estrogen discovery could shed new light on fertility problems

December 12, 2017
Estrogen produced in the brain is necessary for ovulation in monkeys, according to researchers at the University of Wisconsin-Madison who have upended the traditional understanding of the hormonal cascade that leads to release ...

Time of day affects severity of autoimmune disease

December 12, 2017
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between ...

3-D printed microfibers could provide structure for artificially grown body parts

December 12, 2017
Much as a frame provides structural support for a house and the chassis provides strength and shape for a car, a team of Penn State engineers believe they have a way to create the structural framework for growing living tissue ...

Team identifies DNA element that may cause rare movement disorder

December 11, 2017
A team of Massachusetts General Hospital (MGH) researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism (XDP). Occurring only ...

Protein Daple coordinates single-cell and organ-wide directionality in the inner ear

December 11, 2017
Humans inherited the capacity to hear sounds thanks to structures that evolved millions of years ago. Sensory "hair cells" in the inner ear have the amazing ability to convert sound waves into electrical signals and transmit ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.