Skeletal muscle-targeted gene therapy for Pompe disease

Duke University, Durham NC

Investigators

Abstract

SUMMARY OF WORK: Correction of skeletal muscle remains a major challenge for the treatment of Pompe disease (PD, also known as glycogen storage disease type II), an inherited lysosomal storage disorder (LSD) caused by acid alpha- glucosidase (GAA) deficiency that leads to the buildup of lysosomal glycogen in skeletal muscle, heart, and the brain. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Alglucosidase alfa) is the current standard of care but has little effect on skeletal muscles. Insulin-like growth factor 2-tagged hGAA (IGF2- hGAA, reveglucosidase alfa) greatly improved the efficiency of enzyme uptake in skeletal muscles via IGF2 receptor mediated endocytosis, however, hypoglycemia caused by the off-target binding of the IGF2 moiety to the insulin and IGF1 receptors were frequently observed in patients. AAV gene therapy has shown promise for PD with successful translation to early phase clinical trials. Direct muscle gene therapy requires administration of very high doses of AAV vectors that can cause significant hepatotoxicity and genotoxicity; liver-depot gene therapy relying on secretion of hGAA from liver-specific transgene expression requires lower vector doses but has limited effect on skeletal muscles (similar to ERT). Hence, there is a critical unmet need for an improved therapy for PD that can correct the genetic defects in skeletal muscles. In absence of an effective therapy, patients with PD will continue to experience progressive neuromuscular dysfunctions accompanied by increased morbidity and mortality. In this application, we aim to develop an improved AAV gene therapy over current approaches for PD with enhanced efficacy in skeletal muscle and the brain using a mouse model of PD. We hypothesize that site-specific mutagenesis of IGF2-hGAA to prevent its off-target binding will reduce the adverse effects, and thereby increase its safety and clinical translatability for the treatment of PD. We will first identify a lead clinical candidate AAV-hGAA vector with a modified IGF2-hGAA transgene that can be used for liver-depot gene therapy in adult patients (Aim 1). We will next identify a lead clinical candidate AAV-hGAA vector using a combination of a high potency ubiquitous immunotolerizing promoter and a high potency MyoAAV capsid that can be used for muscle gene therapy in both infant and adult patients (Aim 2). Data generated from the proposed studies will lay the foundation for translating these innovative gene therapy approaches to patients with PD. Modification of IGF2-hGAA will reduce the adverse effects and increase the safety, efficacy, and clinical translatability. This approach can be broadly applied to other lysosomal storage diseases in the context of AAV gene therapy and/or ERT. The development of muscle gene therapy for PD will increase the efficacy in correcting skeletal muscles and lower the risk of high-dose vector induced toxicities, and this treatment approach can be adapted for gene therapy in other inherited metabolic disorders that affect skeletal muscles.