Generation of porcine large animal models for FSHD therapeutic development and preclinical testing

Budget

US$2,240,000
FSHD Canada Foundation Contribution: US$1,240,000

Lay Abstract

Investigators: Peter L. Jones Lab; University of Nevada, Reno School of Medicine

The primary therapeutic target in all forms of FSHD is DUX4-fl mRNA and DUX4-FL protein, and animal models of FSHD should be based on DUX4-fl expression. We have previously generated the first viable and fertile transgenic FSHD-like mouse, FLExDUX4, that conditionally expresses DUX4-fl and produces a DUX4-induced FSHD-like phenotype. The goal of this proposal is to use similar technology to generate large animal models of FSHD for preclinical validation of a wide range of potential FSHD therapeutic approaches using minipigs. We will generate three minipig models, 1) the FLExDUX4 minipig, which contains the human DUX4 gene under conditional regulation in skeletal muscles, and 2) the FSHD1 minipig, which contains the human FSHD region of chromosome 4q35 and 3.5 D4Z4 repeat units, and 3) an FSHD2 minipig with a D4Z4 array and a pathogenic SMCHD1 mutation. Successful completion of this project will expedite advancement of therapeutic approaches to the clinic by providing vital tools for assessing preclinical efficacy, safety, toxicology, and dosing in a more human relevant system.