Gene therapy in neuromuscular disorders

Mendonça, Rodrigo Holanda; Zanoteli, Edmar

doi:10.1590/0004-282X-ANP-2022-S135

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Sumário

MUSCLE AND NEUROMUSCULAR JOINT DISORDERS • Arq. Neuro-Psiquiatr. 80 (5 Suppl 1) • May 2022 • https://doi.org/10.1590/0004-282X-ANP-2022-S135 copy

Gene therapy in neuromuscular disorders

Terapia gênica nas doenças neuromusculares

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Monogenic neuromuscular disorders are potentially treatable through gene therapy. Using viral vectors, a therapeutic transgene aims to restore normal levels of a protein not produced by the defective gene, or to silence a gene whose expression leads to toxic effects. Spinal Muscular Atrophy (SMA) is a good example of a monogenic disease that currently has an AAV9-based vector gene therapy as a therapeutic option. In this review, we intend to discuss the viral vectors and their mechanisms of action, in addition to reviewing the clinical trials that supported the approval of gene therapy (AVXS-101) for SMA as well as neuromuscular diseases that are potentially treatable with gene replacement therapy.

Keywords:
Genetic Therapy; Dependovirus or Adeno-Associated Virus (AAVs); Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein; Genetic Vectors

Study/ Identifier in clinicaltrials.gov/ Date started	Phase study and Description	Target population and inclusion criteria	Sample size	Endpoints and results (when available)
AVXS-101-CL-101/ NCT02122952/ 2014	Phase 1, Open-Label, two experimental arms (low and high dose) of IV single-dose AVXS-101	SMA type 1 with two copies of SMN2 up to six or nine months age	N=15 (3 in low dose cohort and 12 in high dose cohort)	Safety and tolerability/ All patients in high dose (N=12) were event-free* and 10/12 sitting
START/ NCT03421977/2017	Observational, long-term follow-up	Patients from AVXS-101-CL-101 gene replacement therapy clinical trial for SMA Type 1	N=13 (10 patients from previous high cohort)	Long term safety data / 6/10 pt sitting, 2/10 pt standing, 2/10 pt walking in 5 years follow-up- ONGOING
AVXS-101-CL-303 or STR1VE-US/ NCT03306277/ 2017	Phase 3, Open-Label, Single-Arm, of IV single-dose AVXS-101	SMA type 1 with one or two copies of SMN2 up to 6 months of age	N=22	13 pt (59%) sitting for 30 sec up to 18m and 90.9% of event-free* survival
STR1VE-EU/ NCT03461289/ 2018	Phase 3, Open-Label, Single-Arm, of IV single-dose AVXS-101	SMA type 1 with one or two copies of SMN2 up to 6 months of age	N=33	14 pt (44%) sitting for 10 sec up to 18m / 31 pt (97%) are event-free* at 14m of age
SPR1NT/ NCT03505099/ 2018	Phase 3, Open-Label, Single-Arm, of IV single-dose AVXS-101	Pre-symptomatic patients with two or three copies of SMN2 up to 42 days (6 weeks) of live at dosing date	N=30 (cohort 1: two copies of SMN2 and cohort 2: three copies of SMN2)	All pt event-free* at 14m of age and 11/15 (79%) sitting for 30 Sec (cohort 1)/ 8/15 pt standing for 3 sec and 6/15 walking (cohort 2)
STRONG/ NCT03381729/2017	Phase 1, Open-Label, dose-compared study of intrathecal single-dose AVXS-101	SMA type 2, with three copies of SMN2, older than 6m and up to 5 years old	N=33 (3 different experimental cohorts: dose A, B and C)	ONGOING - determine optimal dose, standing ability and change in HFMSE/ walking ability and change in ventilation support
OFELIA/ NCT05073133/ 2021	Phase 4, Open-label, single-arm of IV single-dose AVXS-101	Symptomatic SMA (any type) with any copy of SMN2 up to 24m of age and Weight ≤17 kg.	N=16	ONGOING - AEs and SAEs, changes in vital signs, cardiac safety, and laboratory results/ development of motor milestones

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[1] Correspondence:
Rodrigo Holanda Mendonça; Email: rodrigo.holanda@hc.fm.usp.br.