Potentiation of Neuromuscular Transmission As a Therapeutic Strategy to Improve Motor Function in Spinal Muscular Atrophy By
Title page Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophy by Kristine Susan Ojala B.A. Psychology, California State University, Long Beach, 2011 Submitted to the Graduate Faculty of the Dietrich School of Arts & Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 Committee page UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS & SCIENCES This dissertation was presented by Kristine Susan Ojala It was defended on July 28, 2020 and approved by Anne-Marie Oswald, Associate Professor, University of Pittsburgh Jon W. Johnson, Professor, Department of Neuroscience, University of Pittsburgh Zachary P. Wills, Assistant Professor, Department of Neurobiology, University of Pittsburgh Christopher Donnelly, Assistant Professor, Department of Neuroscience, University of Pittsburgh Christine J. DiDonato, Associate Professor, Department of Pediatrics, Northwestern University Dissertation Director: Stephen D. Meriney, Professor, Department of Neuroscience, University of Pittsburgh ii Copyright © by Kristine Susan Ojala 2020 iii Abstract Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophy Kristine Ojala, PhD University of Pittsburgh, 2020 Spinal Muscular Atrophy (SMA) is a genetic disease caused by a null mutation of the SMN1 gene. Loss of SMN1 results in low levels of a protein called Survival of Motor Neuron (SMN), which is a protein that is critical for neuromuscular development. The first FDA-approved treatment for SMA utilizes intrathecal injections of an antisense oligonucleotide (ASO) to increase expression of SMN. Despite the immense excitement for this treatment, however, preliminary clinical observations and studies in SMA mouse models indicate persistent neuromuscular weakness, which reveals the need for an additional symptomatic treatment that targets neuromuscular function.
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