TY - JOUR
T1 - Gene-Targeting Therapeutics for Neurological Disease
T2 - Lessons Learned from Spinal Muscular Atrophy
AU - Ravi, Bhavya
AU - Chan-Cortés, Michelle Harran
AU - Sumner, Charlotte J.
N1 - Funding Information:
C.J.S. is a consultant to Avexis, Biogen, Genentech, Roche, PTC Therapeutics, and Ionis Pharmaceuticals. C.J.S. receives grant funding from Roche. C.J.S. is an Associate Editor at the Journal of Clinical Investigation and an editor of Spinal Muscular Atrophy: Disease Mechanisms and Therapeutics.
Funding Information:
This work was supported by funding to C.J.S. from The SMA Research Team, Cure SMA, and the National Institutes of Health (R01 NS09677 and R01 NS062269).
Publisher Copyright:
© 2021 by Annual Reviews. All rights reserved.
PY - 2021/1/27
Y1 - 2021/1/27
N2 - The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.
AB - The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.
KW - Spinal muscular atrophy
KW - antisense oligonucleotide
KW - biomarkers
KW - gene therapy
KW - small molecules
UR - http://www.scopus.com/inward/record.url?scp=85100208498&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100208498&partnerID=8YFLogxK
U2 - 10.1146/annurev-med-070119-115459
DO - 10.1146/annurev-med-070119-115459
M3 - Review article
C2 - 33502897
AN - SCOPUS:85100208498
SN - 0066-4219
VL - 72
SP - 1
EP - 14
JO - Annual review of medicine
JF - Annual review of medicine
ER -