Heavy-duty virus for the treatment of hereditary myodystrophy
Recently, scientists have made significant progress in developing methods of gene therapy for various hereditary diseases, however, in some cases, the use of traditional gene therapy approaches is impossible due to the large size of target genes. Apparently, the researchers of the National Children's Clinic, working under the guidance of Dr. Louise Rodino-Klapac (Louise R. Rodino-Klapac), managed to solve this problem. One of the possible directions of application of the method developed by them is the treatment of a group of dysferlinopathies and other hereditary dystrophies of muscle tissue.
Dysferlinopathy is a group of incurable diseases caused by mutations in the gene encoding the protein dysferlin. These diseases are usually diagnosed after the age of 20, and by about 35, about a third of such patients can only move with the help of a wheelchair.
Gene therapy using adeno-associated viruses as therapeutic vectors was considered as a potential approach to the treatment of patients with hereditary myodystrophy. Positive results were obtained during a clinical study of gene therapy for a similar pathology – pelvic girdle type 2D myodystrophy caused by a mutation of a small gene encoding the alpha-sarcoglycan protein.
However, the size of the dysferlin gene does not allow it to be packaged into existing viral vectors. The researchers tried to circumvent this problem by using smaller versions of large genes or two or more viral vectors to deliver a full-fledged version of the gene, but in this way they could not achieve the expression of the entire gene. Moreover, an increase in viral load is fraught with the manifestation of undesirable side effects.
In 2008, the AAV5 serotype of the adenoassociated virus was identified, allowing it to pack transcripts of large genes into it. Attempts to use this serotype to transport the dysferlin gene were successful, and as part of their latest work, the authors introduced the obtained therapeutic viral vectors directly into the diaphragm and leg muscles (intramuscularly and into the vessels) of mice without a target gene. Both intramuscular and intravascular administration ensured the expression of the full version of the dysferlin gene in the muscle cells of the diaphragm and legs of animals. Moreover, it ensured the restoration of membrane insufficiency characteristic of muscle cells that do not have the dysferlin gene.
The researchers believe that the approach they have developed opens up new prospects in the treatment of hereditary neuromuscular diseases caused by mutations of large genes, including Duchenne myodystrophy - the most common severe muscular dystrophy of childhood. Currently, they are developing a plan for conducting clinical trials of gene therapy conducted to restore functional insufficiency of muscle tissue in patients with dysferlinopathy.
Article by William E. Grose et al. Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer is published in the journal PLoS ONE.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Nationwide Children's Hospital:
New Gene Transfer Strategy Shows Promise for Limb Girdle and Other Muscular Dystrophies.
10.07.2012