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

J Hordeaux,J Pailloux,C Ciron,C Huchet,M Fusellier,M Ledevin,C Babarit,B Dequéant,C Caillaud,M-A Colle,C Robveille,Y Mallem,F Jamme,L Lagalice,J Deniaud,P Costiou,Q Pascal,L Dubreil

doi:10.1186/s40478-017-0464-2

Abstract

Pompe disease is a lysosomal storage disorder caused by acid-α-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.

Highlights

Pompe disease, known as type II glycogenosis, is a lysosomal storage disease (LSD) caused by mutation in the acid-α-glucosidase (GAA) gene
Our results show that a single intrathecal delivery of AAVrh10- or AAV9-CAG-hGAA to 1 month old 6neo/ 6neo mice enable significant and sustained neurologic and neuromuscular correction for 1 year that correlates with central nervous system (CNS) lysosomal pathology reversion
We verified prior to the in vivo experiments that the recombinant GAA coded by our plasmid was correctly processed, secreted and endocytosed in vitro by using infantile Pompe disease fibroblasts grown in the presence of medium from CAGhgaa transfected HEK293 cells (Additional file 1: Figure S1)

Summary

Introduction

Known as type II glycogenosis, is a lysosomal storage disease (LSD) caused by mutation in the acid-α-glucosidase (GAA) gene. In classic infantile Pompe disease, the severe GAA activity loss causes multi-system and early-onset glycogen storage, especially within the heart and muscles, and early death from cardiorespiratory failure [7]. The specific implication of phrenic motor neurons in the pathophysiology of the respiratory failure has been demonstrated in a mouse model of Pompe disease [18, 23, 37, 44, 65]. These results suggest that a global cardiac, muscular, and CNS targeting therapy is needed to fully reverse the phenotype of infantile Pompe disease.

Methods

Results

Conclusion