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Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophy

Ojala, Kristine (2020) Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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 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 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 increasing 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 efficaciousness of a novel treatment that complements current approaches by addressing persistent deficits after ASO therapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ojala, Kristinekristine.takes.cellfies@pitt.edukso120000-0002-8298-2233
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMeriney, Stephenmeriney@pitt.edumeriney
Committee MemberOswald, Anne-Marieamoswald@pitt.eduasmoswald
Committee MemberJohnson, Jonjjohnson@pitt.edujjohnson
Committee MemberDonnelly, Chrischrisdonnelly@pitt.educhrisdonnelly
Committee MemberWills, Zacharyzpwills@pitt.eduzpwills
Committee MemberDiDonato,
Date: 16 September 2020
Date Type: Publication
Defense Date: 28 July 2020
Approval Date: 16 September 2020
Submission Date: 23 July 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 217
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: spinal muscular atrophy, calcium, neuromuscular junction, synapse, medicine, preclinical research
Date Deposited: 16 Sep 2020 14:41
Last Modified: 16 Sep 2020 14:41

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