Moving towards treatments for spinal muscular atrophy: hopes and limits.
Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches.
a 1 University of Cologne, Institute of Human Genetics, Institute for Genetics, Center for Molecular Medicine Cologne , Kerpener Street 34, 50931 Cologne, Germany +49 221 478 86464 ; +49 221 478 86465 ; brunhilde.wirth@uk-koeln.de.
Brunhilde
B
Wirth
Martine
M
Barkats
Cecile
C
Martinat
Michael
M
Sendtner
Thomas H
TH
Gillingwater
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007231:Infant, Newborn; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
SMN1; SMN2; antisense oligonucleotide therapy; gene modifier; gene therapy; neonatal screening; neuromuscular disorder; pharmacotherapy; spinal muscular atrophy