Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD

Molecular Therapy: Methods & Clinical Development

Allison M. Fowler¹  Scott Q. Harper¹  Lindsay M. Wallace¹  Danielle A. Griffin¹  Nizar Y. Saad¹  Zarife Sahenk¹  Nettie K. Pyne¹  Jocelyn O. Eidahl¹  Jacqueline S. Domire¹  Louise R. Rodino-Klapac¹  Adam C. Herman² 

[1] Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA;Research Information Solutions and Innovation Infrastructure, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA;

关键词: gene therapy;    RNA interference;    RNAi;    adeno-associated viral vectors;    AAV;    facioscapulohumeral muscular dystrophy;    FSHD;    DUX4;    microRNA;   

DOI  :  10.1016/j.omtm.2017.12.005

来源: DOAJ

【 摘 要 】

RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.

【 授权许可】

Unknown