Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2017 Sep 22

PMID 28932756

Citations 20

Authors

Rita Ferla

Marialuisa Alliegro

Jean-Brice Marteau

Margherita DellAnno

Edoardo Nusco

Severine Pouillot

Stefania Galimberti

Maria Grazia Valsecchi

Vincent Zuliani

Alberto Auricchio

Affiliations

Soon will be listed here.

Abstract

In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG. produced under good manufacturing practice-like conditions. No toxicity was observed in AAV-treated mice, except for a transient increase in alanine aminotransferase in females and thyroid epithelial hypertrophy. AAV2/8.TBG. biodistribution and expression confirmed the liver as the main site of both infection and transduction. Shedding and breeding studies suggest that the risk of both horizontal and germline transmission is minimal. An AAV dose-response study in MPS VI mice was performed to define the range of doses to be used in the clinical study. Overall, these data support the non-clinical safety and efficacy of AAV2/8.TBG. and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI.

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