Gene therapy developed to treat limb-girdle muscular dystrophy

A new gene therapy approach has shown promise in a preclinical mouse model for treating limb-girdle muscular dystrophy 2B (LGMD2B), a rare genetic disorder which causes severe muscle weakness.

Scientists at the Children's National Hospital in Washington DC have developed a new approach that avoids the need for delivering a large gene or giving a large vector dose to target the muscles. Testing their new approach over a 12-week study period, they determined that a single, low-dose injection of a gene therapy vector led to the repair of injured muscle fibres, improved muscle strength and decreased degeneration.

'Currently, patients with LGDM2B have no gene or drug-based therapies available to them, and we are amongst the few centres developing therapeutic approaches for this disease', said Dr Jyoti Jaiswal, lead investigator.

Affecting fewer than 1 in every 100,000 people, LGDM2B is caused by a recessive mutation in the gene for dysferlin, a protein involved in repairing muscle cell membranes after injury. The mutation produces a shortened version of the protein which is subsequently degraded. Loss of dysferlin prevents healing of the muscle membrane, making everyday activities such as walking and climbing stairs extremely difficult.

Gene therapy usually involves replacing the faulty gene with a functioning copy, delivered into cells using an adeno-associated virus (AAV). However, previous attempts of treating LGMD2B have been hampered by the size of the dysferlin gene, which is too large to fit inside a single AAV. Scientists have tried splitting the gene in two and delivering the two parts separately, but this requires a large viral load which can trigger an adverse immune response.

Following on from their previous research, where the scientists discovered that dysferlin repairs the cell membrane of a muscle cells by helping lysosomes attach to the damaged muscle cell membrane, and secreting acid sphingomyelinase (ASM), a key enzyme in membrane repair. A deficit of dysferlin in individuals with LGMD2B prevents the release of ASM in injured muscles.

Hence, the scientists inserted the human ASM gene, which is four times smaller than the dysterlin gene, into a liver-specific AAV vector and injected into mice. The human ASM protein was secreted in the liver, and subsequently delivered to the muscles via blood circulation. Publishing their results in the Journal of Clinical Investigation, their findings established that the human ASM-AAV gene therapy improved muscle cell membrane repair in LGMD2B.

Dr Jaiswal concluded: 'We are working to further enhance the efficacy of this approach and perform a longer-term safety and efficacy study to enable the clinical translation of this therapy'. If successful, it could lead to the first effective gene therapy for the condition and could prove beneficial to other disorders of the muscle membrane, including Niemann-Pick disease type A.