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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. Thus, supplemental strategies are required to address the neuromuscular deficits that remain after ASO therapy. In our preclinical investigations, we have tested a calcium channel gating modifier (GV-58), which significantly increases transmitter release from weakened motor nerve terminals, in combination with a potassium channel blocker (3,4-diaminopyridine; 3,4-DAP). 3,4-DAP is a drug commonly prescribed to patients with specific motoneuron diseases, but scientists have debated channel selectivity and concentration-response effects. To address these questions, my colleagues and I have characterized the mechanism of action of 3,4-DAP at neuromuscular junctions across two species (Chapter 2). Our results have provided novel insight into the concentration-dependent effects of 3,4-DAP on presynaptic voltage-gated potassium iv channels, as well as physiological effects on presynaptic action potentials and the magnitude of transmitter released. We next provide proof of principle that 3,4-DAP can be combined with GV-58 to increase strength and improve neuromuscular function in an SMA model mouse (Chapter 3). We have found that GV-58 alone is an excellent therapeutic candidate to restore neuromuscular function and increase strength in more mild forms of SMA, but severe forms of SMA optimally benefit from GV-58 combined with 3,4-DAP. The preclinical investigations contained within this dissertation provide the initial research necessary to explore the efficacy of a novel treatment that complements current approaches by addressing persistent deficits after ASO therapy. v Table of contents Preface ......................................................................................................................................... xiii 1.0 Introduction ............................................................................................................................. 1 1.1 Clinical manifestation of spinal muscular atrophy: Description and classification of SMA types ............................................................................................................................. 2 1.1.1 SMA type 0 ...........................................................................................................3 1.1.2 SMA type 1 ...........................................................................................................4 1.1.3 SMA type 2 ...........................................................................................................5 1.1.4 SMA type 3 ...........................................................................................................6 1.1.5 SMA type 4 ...........................................................................................................7 1.2 The impact of motor impairment on quality of life ..................................................... 8 1.3 The diagnostic journey of SMA ................................................................................... 10 1.4 Survival of Motor Neuron (SMN) protein .................................................................. 12 1.4.1 A tale of two genes: SMN1 & SMN2 .................................................................13 1.4.2 Cellular function of the SMN protein ..............................................................16 1.4.3 Temporal requirements of SMN during development ...................................19 1.5 Animal models versus humans: Cautious interpretation of disease mechanisms .. 22 1.6 Cellular and molecular spinal cord pathology caused by SMN deficiency ............. 25 1.6.1 Pathology of cells in the spinal cord .................................................................26 1.6.2 Neuromuscular development in the presence and absence of adequate SMN expression .....................................................................................................................29 1.6.2.1 Neuromuscular development is regulated by synaptic activity ......... 29 vi 1.6.2.2 Neuromuscular pathology caused by SMN deficiency ....................... 36 1.6.3 Pathophysiology caused by SMN deficiency in other tissues .........................46 1.7 Neuromuscular junctions are critical therapeutic targets in the treatment of SMA .............................................................................................................................................. 48 1.7.1 When is the optimal temporal intervention window to stabilize and protect NMJs? ..........................................................................................................................49 1.7.2 The therapeutic quest to cure SMA ..................................................................50 1.7.3 SMN-based therapies for SMA .........................................................................51 1.7.3.1 Nusinersen: an antisense oligonucleotide (ASO) ................................ 52 1.7.3.2 Onasemnogene Abeparvovec-Xioi: a self-complimentary adeno- associated virus (scAAV9) ................................................................................. 56 1.7.3.3 The advent of new SMN-dependent treatments ................................. 59 1.7.4 SMN-independent therapies ..............................................................................60 1.7.4.1 Neuroprotective strategies .................................................................... 60 1.7.4.2 Muscle-directed strategies ..................................................................... 63 1.7.4.3 Drugs targeting neuromuscular transmission ..................................... 64 1.7.4.4 Endogenous SMN-independent protective modifiers ......................... 65 1.7.4.5 Physical therapy strategies .................................................................... 67 2.0 3,4-Diaminopyridine broadens action potentials to increase transmitter release at the neuromuscular junction independent of Cav1 calcium channels .................................... 69 2.1 Introduction .................................................................................................................. 69 2.2 Methods ......................................................................................................................... 72 2.2.1 Ethics statement .................................................................................................72 vii 2.2.2 Tissue preparation .............................................................................................73 2.2.3 Intracellular microelectrode electrophysiology ...............................................73 2.2.4 Voltage imaging ..................................................................................................74 2.2.5 Whole-cell perforated patch clamp electrophysiology ...................................77 2.2.6 Statistical analysis ..............................................................................................79 2.3 Results ............................................................................................................................ 80 2.3.1 3,4-DAP dose-dependently increases neuromuscular transmission independent of Cav1 channels ...................................................................................80 2.3.2 3,4-DAP effects on the presynaptic AP waveform at the NMJ ......................86 2.3.3 3,4-DAP effects on Kv3 potassium channels ....................................................92 2.4 Discussion .....................................................................................................................
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