The limb-girdle muscular dystrophies (LGMD) encompass a number of rare genetic disorders that inhibit maintenance and repair processes in muscle cells, leading to weakness and eventual wasting of skeletal and cardiac muscle. A major challenge facing LGMD research is its clinical scope; there is an abundance of mutations associated with the disease, each one requiring a unique treatment tailored towards the affected gene. We have worked to develop a system of in vitro cellular models of LGMD mutations using myofibers differentiated from two sources: human embryonic stem cells (ESCs) with a knock-in of the patient variant, and induced pluripotent stem cells (iPSCs) derived from patient fibroblasts. The CRISPR-modified ESC line enables isolated study of LGMD-associated variants through genetic modification of otherwise wild-type cells, to confirm the suspected causality of the mutation. Our aim is to produce a library of CRISPR-engineered human ESC- and iPSC-derived fibroblast lines for known LGMD genes, with the purpose of further testing avenues for therapeutic drug screens.
PROJECT: An in vitro model of limb-girdle muscular dystrophy (LGMD) patient mutations
The Broad Institute is more than a facility that performs cutting-edge research – it is a community of world-class scientists who care deeply about their work, their colleagues, and the impact they have on the future. Working alongside them helped me to improve my skills as a researcher while making meaningful contributions to the field. I can say without hesitation that the relationships I was able to establish while a part of this program are invaluable to me, and will stand for years to come.