Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease

Authors
Hordeaux J1,2,3, Dubreil L1,2, Robveille C1,2, Deniaud J1,2, Pascal Q1,2, Dequéant B1,2, Pailloux J1,2, Lagalice L1,2, Ledevin M1,2, Babarit C1,2, p Costiou, F Jamme, M Fusellier, Y Mallem, C Ciron, C Huchet, C Caillaud, MA Colle

Lab
Nantes-Atlantic National College of Veterinary Medicine, France

Journal
Acta Neuropathological Communiations

Abstract
Pompe disease is a lysosomal storage disorder caused by acid-_-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)