Matrix Bound Nanovesicles (MBV) as a Therapy for FSHD

Budget

US$47,619

Lay Abstract

Investigator: Dr. George Hussey, University of Pittsburgh

Regenerative Medicine provides an alternative FSHD treatment strategy for promoting new tissue growth using Extracellular Matrix (ECM) bioscaffolds.

ECM bioscaffolds serve as a biochemical framework and modulate the local tissue environment to stimulate growth by activating pro-regenerative immune populations and recruiting endogenous stem cell populations, ultimately resulting in increased muscle repair. ECM bioscaffolds have been extensively investigated in in-vitro studies, preclinical in-vivo models of volumetric muscle loss (VML) and Duchenne Muscular Dystrophy (DMD), and in a recent human cohort study involving the use of ECM bioscaffolds in 13 patients with VML. Cumulatively, outcomes from these preclinical and clinical studies have shown partial restoration of functional skeletal muscle tissue and support the translational aspects of an ECM- based approach as a therapy for FSHD.

Recently, we have identified the molecular components of ECM bioscaffolds mediating its regenerative effects. New evidence now shows that degradation of the scaffold material and subsequent release of matrix-bound-nanovesicles (MBV), that harbor bioactive components, are critical for the activation of a reparative and anti-inflammatory immune environment and downstream constructive remodeling of skeletal muscle tissue. MBV are nanometer sized vesicles that contain biologically active signaling cytokines, growth factors and pro-resolving lipids. MBV can be purified from ECM bioscaffolds and have been shown to independently promote stem cell differentiation and activation of a pre-remodeling anti-inflammatory immune cell phenotype. Given their nanometer size, MBV can be injected directly into diseased or injured muscle tissue to facilitate the constructive remodeling of dystrophic muscle tissue.

Our objective is to gain mechanistic insight into the effect that MBV signaling molecules have on the immunobiology behind skeletal muscle regeneration in FSHD cells. Our experimental design will allow for the first in-depth molecular characterization of the genes and transduction mechanisms regulated by MBV in FSHD cells and will greatly aid in our understanding of the molecular mechanisms by which MBV facilitates the processes involved in the wound healing response in FSHD cells.

Importantly, this study will evaluate clinical grade MBV that have been produced under cGMP-specifications. The findings from the proposed studies thus have the potential for immediate clinical translation and may enable augmentation of the restorative efficacy of existing ECM-based and non-ECM based approaches to treat patients with FSHD.