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Abstract

Pompe disease (glycogen storage disease type II) is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency leading to progressive accumulation of glycogen in the heart, muscles, and central nervous system (CNS). The disease manifests as a fatal cardiomyopathy in infantile form. Cardiac correction by enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The emergent neurologic phenotype and the persistence of muscular weakness in survivors are currently partly attributed to CNS glycogen storage, uncorrected by ERT.

We hypothesized that CNS correction by gene therapy using recombinant Adeno-associated viruses (rAAV) encoding the GAA transgene would alleviate the neurologic manifestations of the disease and would lead to an improvement of the neuromuscular function.

To address this question, we first demonstrated using a reporter gene that the injection of rAAV in the cerebrospinal fluid (intrathecal injection) enables efficient and diffuse transduction of the CNS. GAA-KO 6neo mice were next treated with intrathecal AAV-gaa at one month and their neuromuscular function was assessed for one year. We demonstrate a significant functional neurologic correction in treated animals and a partial restoration of the muscular strength. The entire CNS shows enzymatic, biochemical and histological correction. Muscle glycogen storage is not cleared by the treatment, thus suggesting that the partial restoration of strength is directly related to the CNS correction. This widespread CNS cure and its impact on the global neuromuscular function offer new perspectives for the management of patients.

PhD supervisor : Marie-Anne Colle

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Associated publications:

• Thesis
• Articles

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