Matrix Bound Vesicles for the Treatment of DUX4-mediated Muscle Pathology

Budget

US$10,371

Lay Abstract

Investigators: Collaborative study between Dr. Michael Kyba (UMN) and Dr. Stephen Badylak (UPMC)

This study will investigate the effects of treating muscle with GMP produced matrix-bound vesicles (MBVs) in the iDUX4pA/HSA mouse model for Facioscapulohumeral muscular dystrophy (FSHD). The laboratory of Stephen Badylak at the University of Pittsburgh Medical Center and the McGowan Institute for Regenerative Medicine will provide the MBV and we will treat iDUX4pA/HSA mice, obtain muscle tissue from treated and control mice, and send these in blinded fashion back to Dr. Badylak’s laboratory at the McGowan Institute for Regenerative Medicine for analysis. After each experiment has been analyzed, the blinded code will be broken and the effect of the treatment determined.

The experiments will proceed in a phased approach. The initial study will employ group sizes of n=6 mice, fed doxycycline chow to induce DUX4 expression and muscle pathology starting at Day 0, and being treated with 1E10 MBVs in 100 μL by intravenous injection at Days 0, 2, 4, and 6. Mice will be euthanized at day 14 and muscle tissue obtained and sent to the Badylak laboratory. Muscle sections will be evaluated for quantitative markers of fibrosis (Sirius Red staining), as well as for gross histology (H&E staining).

Follow-up studies will employ modifications in replication of the basic treatment regimen, depending on results obtained. Group sizes may be altered based on effect sizes and observed p-values. IP and Intra-muscular delivery may be tested if effects are not seen with intravascular delivery. Number of injections, frequency of injections, and duration of doxycycline exposure may also be modified.

The objective is to determine whether and by what delivery method and disease induction protocol MBVs reduce the DUX4-induced pathology in the iDUX4pA/HSA mouse model for FSHD.

The current project envisions studies over a 5 month period (Feb 2023 – June 2023) and will support animal costs and technician time.