Evaluation of Readministration of a Recombinant Adeno-Associated Virus Vector Expressing Acid Alpha-Glucosidase in Pompe Disease: Preclinical to Clinical Planning
| Autor: | Janet M. Benson, Thomas J. Conlon, Manuela Corti, Nathalie Clement, Davis Fuller, Roland W. Herzog, Kaitlyn J. Faris, Barry J. Byrne, Brian Cleaver, Gensheng Wang, Alice F. Tarantal |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Genetic enhancement Genetic Vectors Gene Expression Biology Antibodies Viral medicine.disease_cause Injections Intramuscular Immunomodulation Mice Clinical Protocols Glycogen storage disease type II medicine Animals Humans Immunologic Factors Tissue Distribution Dosing Vector (molecular biology) Adeno-associated virus Research Articles Genetics (clinical) Mice Knockout Glycogen Storage Disease Type II Dependovirus medicine.disease Macaca mulatta Clinical trial Disease Models Animal Retreatment Immunology Acid alpha-glucosidase biology.protein Female Glucan 1 4-alpha-Glucosidase Antibody Rituximab |
| Zdroj: | Human Gene Therapy Clinical Development. 26:185-193 |
| ISSN: | 2324-8645 2324-8637 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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