Gene therapy successful in LGMD2D mice

Published Date
Super Administrator

Successful gene therapy in the mouse model of limb girdle muscular dystrophy type 2D has set the stage for clinical trials to begin.

Research published in July 2008 by Jerry Mendell (Ohio, USA) has reported a successful gene therapy method in the mouse model of limb girdle muscular dystrophy type 2D (LGMD2D). Injection of an AAV virus containing the human alpha-sarcoglycan gene into the mice resulted in the production of the protein that is missing in LGMD2D. Significant amounts of alpha-sarcoglycan protein were produced up to 12 weeks after injection and there was no sign of immune response to the virus. The researchers have started recruiting volunteers for a clinical trial of this gene therapy method.


  • What did the new research show?
  • What does this mean for patients with LGMD2D?
  • Further information and links

What did the new research show?

The genes associated with limb girdle muscular dystrophy (LGMD) generally contain the information for proteins necessary for muscle function, but genetic defects in these genes cause the proteins to be absent or faulty. This leads to weakness in the shoulder and pelvic ‘girdles’ – the large muscles around the top of the arms and legs. There are at least 19 forms of LGMD. The genes involved in 15 of these forms have been identified. LGMD types 2C, 2D, 2E and 2F all involve genes which code for different types of sarcoglycan proteins. The sarcoglycans are important components of the structure of muscle cells.

Mendell’s group of researchers aimed to develop a gene therapy method with the potential to treat individuals with LGMD2D. Gene therapy involves introducing a healthy copy of the mutated gene into cells. To deliver the gene into cells, a virus can be used which has been genetically altered to carry normal human DNA.  Viruses called adeno-associated virus (AAV) are particularly useful for this because they are able to infect human cells but do not cause any disease, and usually only cause mild immune reactions.

The researchers inserted the human alpha-sarcoglycan gene into the AAV1 virus along with a molecular switch that would only allow the alpha-sarcoglycan protein be produced in muscle. This virus was injected into the lower legs of mice which lack alpha-sarcoglycan so represent a model of LGMD2D. The muscles injected with the virus strongly produced the alpha-sarcoglycan protein, even 12 weeks after injection. There was no sign of immune reaction to the injected virus.

In the past, this type of gene therapy approach in the LGMD2D mouse model was reported to be largely unsuccessful, probably due to the occurrence of immune reactions to the injected virus which removed the virus and the cells that had been successfully treated. The success of this new research is likely to be due to the use of a well tolerated type of the virus – AAV1. The virus preparation was also purified more thoroughly prior to injection than in previous studies. The strategy of only allowing the protein to be produced in muscle, and not other cells in the body where it doesn’t belong, may have also improved the virus’ efficiency and avoided immune reactions.

What does this mean for patients with LGMD2D?

Following the publishing of these results, a clinical trial has been initiated in Ohio. They will recruit only 6 patients to begin with who will have the virus injected into one of muscles in the front of the lower leg. The purpose of this initial trial will primarily be to test the safety of the virus before further trials can be conducted.

Although this is a promising step forward for gene therapy of LGMD2D there are still significant hurdles to be overcome. Gene therapy is a very new technology and we don’t know if these viruses will be as successful in humans as they have been in mice. We will watch with interest as the trial for LGMD2D progresses.

Further information and links

Find out more information about limb girdle muscular dystrophy.

More information about the clinical trial can be found at the Muscular Dystrophy Association

The research paper called “Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D” can be found at the Official Journal of the American Academy of Neurology. The paper was published in the journal Neurology which is available by subscription only, so the original article is not freely available. The article is written in technical language with no summary in layman’s terms.

Keep in touch