Evaluation of Readministration of a Recombinant Adeno-Associated Virus Vector Expressing Acid Alpha-Glucosidase in Pompe Disease: Preclinical to Clinical Planning

• DOI: 10.1089/humc.2015.068
• Publication Date: 2015-06-07T08:14:01Z
• Authors: Manuela Corti; Brian Cleaver; Nathalie Clément; Thomas J. Conlon; Kaitlyn J. Faris; Gensheng Wang; Janet Benson; Alice F. Tarantal; Davis Fuller; Roland W. Herzog; Barry J. Byrne
• Keywords: Adeno-associated virus; Biodistribution

A recombinant serotype 9 adeno-associated virus (rAAV9) vector carrying a transgene that expresses codon-optimized human acid alpha-glucosidase (hGAA, or GAA) driven by desmin (DES) promoter (i.e., rAAV9-DES-hGAA) has been generated as clinical candidate for Pompe disease. The rAAV9-DES-hGAA is being developed treatment both early- and late-onset disease, in which patients lack sufficient lysosomal leading to glycogen accumulation. In young patients, the therapy may need be readministered after period of time maintain therapeutic levels GAA. Administration AAV-based gene therapies commonly associated with production neutralizing antibodies reduce effectiveness vector, especially if readministration required. Previous studies have demonstrated ability correct cardiac skeletal muscle pathology Gaa(-/-) mice, an animal model This article describes IND-enabling preclinical supporting program phase I/II trial adult Pompe. These were designed evaluate toxicology, biodistribution, potential injected intramuscularly into tibialis anterior using immune modulation strategy this study. proposed study, six participants disease will enrolled. goal ablate B-cells before initial exposure study agent one leg subsequent same contralateral four months dosing. dosing active accompanied control injection excipient allow blinding randomization dosing, also strengthen evidence from future. Patients act their own controls. Repeated measures, at baseline during three following each assess safety, biochemical, functional impact vector.