September 23, 2020
Alec Smith (University of Washington) “Human stem cell-based models of neuromuscular disease and their application in elucidating underlying mechanisms and screening for novel therapeutic efficacy”
Alec Smith, Ph.D.
University of Washington
“Human stem cell-based models of neuromuscular disease and their application in elucidating underlying mechanisms and screening for novel therapeutic efficacy”
Seminar abstract: Inheritable neuromuscular disorders (NMDs) arise from genetic mutations that lead to dysfunction in either the motor nerves that control voluntary muscle contraction, the sensory nerves that communicate information from peripheral tissues to the brain, the skeletal musculature itself, or a combination of these tissues. Incidence rates encompassing all NMD diagnoses are roughly 72 cases per 100,000 people, with numbers increasing with age. Such conditions can be severely debilitating, with typical symptoms being progressive muscle weakness, numbness, chronic pain, and even death. High incidence rates and a burgeoning aged population, both in the United States and abroad, underscore the dire need for novel therapeutic options designed to alleviate or reverse symptoms arising from these conditions. However, the development of new strategies for targeting NMDs is hindered by a paucity of suitable preclinical models with which to predict therapeutic efficacy in patients. The wide array of affected genes, each typically supporting a number of disease-causing mutations, and the number of cell types and tissues implicated in the various NMD pathologies makes the development of predictive models challenging. Additionally, the inherent differences between humans and other species raise questions relating to the translational and predictive ability of preclinical animal models to accurately describe clinical phenomena. Recent progress in human induced pluripotent stem cell (hiPSC)-derived muscle and neuron production raises the possibility of generating human in vitro models of neuromuscular tissues to circumvent species incompatibility issues and to facilitate analysis of multiple disease-causing mutations within a single platform. However, few cell culture assays currently exist that are capable of providing researchers with data that directly correlate with clinical measurements of NMD pathology, limiting the predictive power of such technologies. My research aims to develop new preclinical, in vitro models that facilitate assessment of functional deficits in human NMDs and enable high-throughput screening of therapeutic efficacy in ameliorating symptoms in these conditions. In this talk, I will highlight my recent work focused on the establishment of human stem cell-based models of motor neurons and skeletal muscle and their incorporation into functional assays for use in mechanistic evaluation of disease etiology and in the testing of novel therapeutics. Specifically, I will discuss an electrophysiological assay for studying Charcot Marie Tooth disease and a 3D contractile assay for modeling distal arthrogryposis syndromes. I will also provide an overview of future directions for this research that focuses on the development of accurate, functional models of the human neuromuscular junction.
host: Beth Buffalo