What is Gene Therapy and can it be used to treat LGMD2B?

Gene therapy is a therapeutic technique for genetic diseases, such as muscular dystrophies, that involves the injection of a patient with a gene carrier called a “vector.” The vector delivers to the patients’ cells a normal copy of the mutated gene to replace the protein whose absence causes the disease.    Gene therapy is a very attractive therapeutic possibility for the treatment of dysferlinopathy (i.e. a muscular dystrophy caused by mutations in the dysferlin gene).  In a recent paper, researchers reported their findings from testing gene therapy in a mouse model of dysferlinopathy (http://www.ncbi.nlm.nih.gov/pubmed?term=grose%20mendell).  In this paper, the researchers describe the addition of a normal copy of the dysferlin gene to the muscle cells of a dysferlin deficient mouse using an adeno-associated virus (AAV) gene vector.  AAV is the preferred gene vector for performing gene therapy, as it has been extensively studied, and does not cause an adverse reaction from the immune system.  Most of the gene therapy trials conducted to date have used AAV vectors.  A challenge specific to transferring dysferlin into muscles is that unlike other genes, the dysferlin gene is too big to fit inside AAV vectors or other possible gene therapy vectors. To overcome that challenge, the researchers divided the dysferlin gene into pieces and loaded the smaller pieces into individual AAV vectors.  When the AAV vectors enter the muscle cells, they release the parts of the dysferlin gene that they carry and the entire dysferlin gene is reassembled from the pieces.  One possible issue with this kind of approach is whether there will be sufficient reassembly of the pieces to make enough functional protein to improve the symptoms of the disease.  In this paper, the researchers showed that mice with dysferlin deficiency were able to express a significant amount of the full length dysferlin protein following AAV treatment and that as a result symptoms of the disease were reduced.


 Before this technique can be tried in human clinical trials, the researchers will need to address safety concerns that apply to gene therapy in general, like making sure the gene gets into the right cells and does not cause toxicity in the recipient. In addition, a safety assessment of delivering pieces of genes that are then reassembled will also be necessary because this approach has not been used in humans before. Thus, regulatory agencies like the US FDA will likely require rigorous testing for several years before Phase I (safety) clinical trials can begin in humans.


 Even given these challenges, the Jain Foundation thinks this approach is promising.  We are optimistic that, given time and the necessary research, an efficacious gene therapy approach specific to dysferlinopathy (LGMD2B/Miyoshi) can be developed and we are committed to helping move this process forward.  An important point to note regarding the application of gene therapy as a therapeutic option is that each individual needs to be genetically diagnosed by the identification of mutations in the dysferlin gene in order to be eligible for such a treatment.  If you are unsure whether or not you have been genetically diagnosed the Jain Foundation can help.  Please contact the Jain Foundation’s Director of Patient Relations, Sarah Shira, at or 425-882-1440 or click here for more information.