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

Autor:	Wallace LM; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Saad NY; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Pyne NK; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Fowler AM; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Eidahl JO; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Domire JS; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Griffin DA; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Herman AC; Research Information Solutions and Innovation Infrastructure, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Sahenk Z; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.; Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, USA., Rodino-Klapac LR; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA., Harper SQ; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2017 Dec 24; Vol. 8, pp. 121-130. Date of Electronic Publication: 2017 Dec 24 (Print Publication: 2018).
DOI:	10.1016/j.omtm.2017.12.005
Abstrakt:	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.
Databáze:	MEDLINE
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