The disease affects between 1-in-100,000 to 1-in-200,000 newborns without regard to sex, but appears to be much more common in people of northern European descent. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective anoctamin 5 gene each from both parents. LGMD2L is a late onset (avg age of 35, range 15-70 years) proximal lower-limb weakness with markedly elevated creatine kinase (a biomarker of muscle injury); usually 10-50 times the upper limit of normal. Joint contractures (tightening) are not a frequent feature in LGMD2L, however they can occur as a consequence of the reduced mobility of these patients. It is not infrequent that one side of the body is more severely affected than the other. The weakness and wasting of the lower limbs can lead to frequent falls, and difficulty in running, climbing stairs, and raising up from the floor. As the condition progresses, patients can also develop some weakness in their arms, resulting in difficulties with lifting heavy objects. The severity of the disease is variable from person to person and even amongst members of the same family. There is not currently any cure or treatment for LGMD2L.
The goal of gene therapy for LGMD2L is to permanently enable the muscle cells to produce the critical anoctamin protein, after intravenous administration of a vector containing the anoctamin 5 gene and a promoter that only turns on the gene in muscle cells. Establishment of anoctamin production in the muscle cells is expected to result in significant improvement in symptoms, with greater improvement toward normal the earlier in the disease the treatment is administered, and with the potential to prevent any symptoms of the disease from occurring when administered to newborns with confirmed LGMD2L from genetic testing.
The L. Rodino-Klapac laboratory developed and validated an animal model of LGMD2L and gene therapy safety and efficacy studies are underway. Progression toward an IND allowing initiation of human clinical trials are expected to continue throughout 2018.