title: Evaluation of Readministration of a Recombinant Adeno-Associated Virus Vector Expressing Acid Alpha-Glucosidase in Pompe Disease: Preclinical to Clinical Planning.
abstract: 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 a human desmin (DES) promoter (i.e., rAAV9-DES-hGAA) has been generated as a clinical candidate vector for Pompe disease. The rAAV9-DES-hGAA vector is being developed as a treatment for both early- and late-onset Pompe disease, in which patients lack sufficient lysosomal alpha-glucosidase leading to glycogen accumulation. In young patients, the therapy may need to be readministered after a period of time to maintain therapeutic levels of GAA. Administration of AAV-based gene therapies is commonly associated with the production of neutralizing antibodies that may reduce the effectiveness of the vector, especially if readministration is required. Previous studies have demonstrated the ability of rAAV9-DES-hGAA to correct cardiac and skeletal muscle pathology in Gaa(-/-) mice, an animal model of Pompe disease. This article describes the IND-enabling preclinical studies supporting the program for a phase I/II clinical trial in adult patients with Pompe. These studies were designed to evaluate the toxicology, biodistribution, and potential for readministration of rAAV9-DES-hGAA injected intramuscularly into the tibialis anterior muscle using an immune modulation strategy developed for this study. In the proposed clinical study, six adult participants with late-onset Pompe disease will be enrolled. The goal of the immune modulation strategy is to ablate B-cells before the initial exposure of the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg four months after initial dosing. The dosing of the active agent is accompanied by a control injection of excipient dosing in the contralateral leg to allow for blinding and randomization of dosing, which may also strengthen the evidence generated from gene therapy studies in the future. Patients will act as their own controls. Repeated measures, at baseline and during the three months following each dosing will assess the safety, biochemical, and functional impact of the vector.
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Manuela
authors.initials: M
authors.lastname: Corti
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Brian
authors.initials: B
authors.lastname: Cleaver
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clément
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Kaitlyn J
authors.initials: KJ
authors.lastname: Faris
authors.affiliation: 2 Applied Toxicology and Gene Therapy Pharm/Tox Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Gensheng
authors.initials: G
authors.lastname: Wang
authors.affiliation: 2 Applied Toxicology and Gene Therapy Pharm/Tox Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Janet
authors.initials: J
authors.lastname: Benson
authors.affiliation: 3 Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, California National Primate Research Center, Davis, California; Department of Pediatrics, University of California, Davis, Davis, California; Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, California.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Tarantal
authors.affiliation: 4 Department of Physical Therapy, University of Florida, Gainesville, Florida.
authors.forename: Davis
authors.initials: D
authors.lastname: Fuller
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.affiliation: 1 Department of Pediatrics and Powell Gene Therapy Center, University of Florida, College of Medicine, Gainesville, Florida.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D002985:Clinical Protocols; D000229:Dependovirus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics* / Q000493:pharmacokinetics; D005087:Glucan 1,4-alpha-Glucosidase / Q000235:genetics*; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D056747:Immunomodulation / Q000187:drug effects; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019233:Retreatment; D000069283:Rituximab / Q000008:administration & dosage; D014018:Tissue Distribution
chemical_list: D000914:Antibodies, Viral; D007155:Immunologic Factors; D000069283:Rituximab; D005087:Glucan 1,4-alpha-Glucosidase