Research
There is a variety of research underway targeted at various forms of LGMD. Methods thought to hold significant promise for an effective treatment include "exon skipping" and gene therapy. Several clinical trials are underway and seeking to apply these methodologies to various limb girdly dystrophies.
GENETHON - LGMD 2C(Gamma-sarcoglycanpathy)
The results of a Phase I clinical trial of gene therapy for limb-girdle muscular dystrophy type 2C were published in the journal Brain in January 2012. The trial started in December 2006 and has been sponsored by Généthon (the not-for-profit research lab created by the French Muscular Dystrophy Association (AFM) and which is funded almost exclusively by donations from France's annual Telethon). The trial at Pitié-Salpêtriere (AP-HP) is being led by principal investigators Professor Serge Herson (Head of the Department of Internal Medicine 1) and Professor Olivier Benveniste (Institute of Myology). The study's primary objective was to evaluate the safety of local injection of increasing doses of an adeno-associated virus (AAV) vector harboring a "healthy" copy of the gene for gamma-sarcoglycan (the defective protein in this disease). Secondary objectives included the assessment of local and systemic immune reactions and the quality of gene transfer in the injected muscles in terms of efficacy, expression and distribution. The trial's results have just been published and were encouraging. Above all, the injections were well tolerated and not associated with adverse physical or biological effects. Immunohistochemical analysis of injected-muscle biopsy specimens showed ?SGC expression in three out the three patients who received the highest dose. Furthermore, in one of these patients (who had received the highest dose of treatment), a western blot assay revealed that normal protein gamma-sarcoglycan was being expressed in the muscle fibers. Thanks to gene therapy, the missing gamma-sarcoglycan protein was being produced anew. In addition to confirming the treatment's lack of toxicity (the study's primary objective), we were able to make progress in other areas, such as trial logistics, immunological aspects and even the optimal dose for treating a set of muscles efficaciously. This result is especially interesting because it means that we have established the dose threshold above which the treatment becomes efficacious. That’s very rare in a Phase I trial".
JERRY MENDELL - LGMD 2D(alpha-sarcoglycanpathy)
Researchers in the US led by Prof. Jerry Mendell have published the results of a gene therapy trial for limb girdle muscular dystrophy type 2D (LGMD2D). Individuals affected by this condition have a fault in their 'alpha-sarcoglycan' gene which contains the instructions for a protein which is essential for muscle function. In this clinical trial three teenagers with LGMD2D had a virus containing a healthy copy of the alpha-sarcoglycan gene injected into a muscle in their foot. Not only was the gene therapy deemed to be safe, a significant amount of alpha-sarcoglycocan protein was produced which persisted for at least three months.
The researchers inserted a healthy copy of the human alpha-sarcoglycan gene into the AAV1 virus along with a molecular 'switch' that would only allow the alpha-sarcoglycan protein to be produced in muscle. This virus was injected into one small muscle in the foot. The same muscle in the other foot was injected with saline (salty water) as a control. Either six weeks (two patients) or 3 months (one patient) after the injection the production of alpha-sarcoglycan protein was assessed.
The muscles injected with the virus strongly produced the alpha-sarcoglycan protein in up to 69% of muscle fibres and was correctly located in the muscle membrane. This in turn restored the structure of a cluster of proteins that is normally found in muscle cells but is missing in muscles that lack alpha-sarcoglycan. This protein cluster is vital for the structure of the muscle fibres.
The results of this phase I clinical trial of gene therapy for LGMD2D are very promising. However, delivery of the gene therapy to the whole body, for example via the blood stream, is required for an improvement in symptoms to be seen in patients. This will be the next step in the development of gene therapy for LGMD2D. Clinical trials will be needed to determine the optimal route of administration, dose and the long term safety of the treatment.
The success of the AAV1 virus to deliver the gene to the muscles in this trial also bodes well for the development of gene therapy for other neuromuscular conditions.
Read more about this topic: Limb-girdle Muscular Dystrophy
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