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

Rita Ferla,Marialuisa Alliegro,Jean-Brice Marteau,Margherita Dell’Anno,Edoardo Nusco,Severine Pouillot,Stefania Galimberti,Maria Grazia Valsecchi,Vincent Zuliani,Alberto Auricchio

doi:10.1016/j.omtm.2017.07.004

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.hARSB 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.hARSB 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.hARSB and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI.

Highlights

IntroductionAdeno-associated viral (AAV) vectors are widely used for in vivo gene therapy applications due to their excellent safety and efficacy profiles in both preclinical and clinical trials.[1,2,3,4,5,6,7,8]We recently developed a gene therapy approach for mucopolysaccharidosis type VI (MPS VI).[9,10,11,12,13,14,15] MPS VI is a rare lysosomal storage disorder (LSD) that is caused by arylsulfatase B (ARSB) deficiency, which results in widespread accumulation and urinary excretion of toxic glycosaminoglycans (GAGs).[16]
We demonstrated that a single systemic administration of a recombinant associated viral (AAV) vector serotype 8 (AAV2/8), which encodes arylsulfatase B (ARSB) under the transcriptional control of the liver-specific thyroxine-binding globulin (TBG) promoter (AAV2/8.TBG.hARSB), results in sustained liver transduction and phenotypic improvement in mucopolysaccharidosis type VI (MPS VI) animal models.[9,11,12,13,14,15]
In the hemophilia B clinical trial, which used i.v. administration of AAV serotype 2 (AAV2)/8 at the same doses we propose to use in our trial, scAAV2/8-LP1-hFIXco vector DNA was detectable in the plasma, saliva, urine, and stool of patients within 72 hr of vector infusion and up to but not after day 20 in all participants; the magnitude and duration of AAV shedding into the plasma, saliva, stool, and urine appeared to be dependent on the dose administered.[2,4]

Summary

Introduction

Adeno-associated viral (AAV) vectors are widely used for in vivo gene therapy applications due to their excellent safety and efficacy profiles in both preclinical and clinical trials.[1,2,3,4,5,6,7,8]We recently developed a gene therapy approach for mucopolysaccharidosis type VI (MPS VI).[9,10,11,12,13,14,15] MPS VI is a rare lysosomal storage disorder (LSD) that is caused by arylsulfatase B (ARSB) deficiency, which results in widespread accumulation and urinary excretion of toxic glycosaminoglycans (GAGs).[16]. Adeno-associated viral (AAV) vectors are widely used for in vivo gene therapy applications due to their excellent safety and efficacy profiles in both preclinical and clinical trials.[1,2,3,4,5,6,7,8]. The study was designed as a phase I/II open-label, dose-escalation study to test both the safety and efficacy of a single systemic administration of AAV2/8.TBG.hARSB at doses ranging between 2 Â 1011 and 2 Â 1012 genome copies (GC)/kg body weight

Methods

Results

Conclusion