Scot Wolfe Receives NIH Grant for Muscular Dystrophy Gene Editing Research
Scot Wolfe, PhD, and Charles Emerson, PhD, professor of neurology and Director of the Wellstone Muscular Dystrophy Program at UMass Chan, have received an exploratory research project (R21) grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to develop and validate a human muscle xenograft platform for evaluating and optimizing genome editing therapies for muscular dystrophies in vivo. The project brings together Wolfe’s expertise in genome editing technologies with Emerson’s expertise in muscle disease biology and patient-derived models.
As proof of concept, the researchers will optimize a prime editing strategy to correct a common mutation associated with a subtype of limb-girdle muscular dystrophy known as LGMDR9 (or LGMD2i), which is caused by mutations in the FKRP gene. They are focusing on the most common FKRP mutation, L276I.
The team will first optimize their prime editing reagents in vitro using an induced pluripotent stem cell (iPSC)-derived model, in which iPSCs generated from a patient with LGMDR9 are differentiated into myotubes. They will perform genome-wide analyses to evaluate the precision of the editing and identify potential off-target effects.
They will then transplant the patient-derived muscle cells into mice to create human muscle xenografts and deliver their optimized prime editing reagents in lipid nanoparticles by direct intramuscular injection or systemic delivery. They will optimize dosing regimens to maximize correction of the FKRP mutation while minimizing off-target editing, and also assess therapeutic efficacy using molecular and cellular measures of disease.
By developing and evaluating a prime editing strategy in the context of a patient-derived muscle xenograft model, Wolfe and Emerson aim to establish a general pathway for translating genome editing therapies to the clinic and contribute to the development of safer, more effective therapies for muscular dystrophies.
