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

National audience

Inglés. Pompe disease (glycogen storage disease type II) is a lysosomal storage disorder caused by acidalpha- 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 poor correction of skeletal muscles in survivors are currently partly attributed to CNS glycogen storage, uncorrected by ERT. We evaluated a gene therapy strategy using the neurotropic and cardiotropic AAV serotype 9 injected intrathecally (ie in the cerebrospinal fluid) to restore GAA activity in the CNS and the heart. GAA-KO mice were injected with AAV9-gaa into the cisterna magna at one month. Their neurologic and motor skills were periodically monitored from three to twelve months by hind limb clasping reflex, brainstem auditory evoked potentials, wire-hang test, and accelerating rotarod; cardiac function was assessed by M-mode echocardiography at 12 months. Glycogen content, GAA activity, and disease-related pathology were assessed in the CNS and heart at end-point. We also used real-time RT-PCR to examine transcriptional markers of cardiomyopathy and denervation atrophy in the heart and muscles respectively. 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, spinal ganglia, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.