Restricted accessResearch articleFirst published online 2023-08
From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis
MillerTM, CudkowiczME, GengeA, ShawPJ, SobueG, BucelliRC, ChiòA, Van DammeP, LudolphAC, GlassJD, AndrewsJA, BabuS, BenatarM, McDermottCJ, CochraneT, CharyS, ChewS, ZhuH, WuF, NestorovI, GrahamD, SunP, McNeillM, FanningL, FergusonTA, FradetteS; and VALOR and OLE Working Group. (2022). Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med, 387:1099–1110.
3.
Aartsma-RusA. (2017). FDA approval of nusinersen for spinal muscular atrophy makes 2016 the year of splice modulating oligonucleotides. Nucleic Acid Ther, 27:67–69.
4.
Aartsma-RusA. (2023). The future of exon skipping for Duchenne muscular dystrophy. Hum Gene Ther, 34:372–378.
5.
CouratierP, LautretteG, LunaJA and CorciaP. (2021). Phenotypic variability in amyotrophic lateral sclerosis. Rev Neurol (Paris), 177:536–543.
6.
RavitsJM and La SpadaAR. (2009). ALS motor phenotype heterogeneity, focality, and spread: Deconstructing motor neuron degeneration. Neurology, 73:805–811.
7.
RentonAE, ChiòA and TraynorBJ. (2014). State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci, 17:17–23.
8.
BrownCA, LallyC, KupelianV and FlandersWD. (2021). Estimated prevalence and incidence of amyotrophic lateral sclerosis and SOD1 and C9orf72 genetic variants. Neuroepidemiology, 55:342–353.
9.
McCampbellA, ColeT, WegenerAJ, TomassyGS, SetnickaA, FarleyBJ, SchochKM, HoyeML, ShabsovichM, SunL, LuoY, ZhangM, ComfortN, WangB, AmackerJ, ThankamonyS, SalzmanDW, CudkowiczM, GrahamDL, BennettCF, KordasiewiczHB, SwayzeEE and MillerTM. (2018). Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest, 128:3558–3567.
10.
MortbergMA, GentileJE, NadafNM, VanderburgC, SimmonsS, DubinskyD, SlaminA, MaldonadoS, PetersenCL, JonesN, KordasiewiczHB, ZhaoHT, VallabhSM and Minikel.EV (2023). A single-cell map of antisense oligonucleotide activity in the brain. Nucleic Acids Res. doi: 10.1093/nar/gkad371
11.
FinkelRS, ChiribogaCA, VajsarJ, DayJW, MontesJ, De VivoDC, YamashitaM, RigoF, HungG, SchneiderE, NorrisDA, XiaS, BennettCF and BishopKM. (2016). Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet, 388:3017–3026.
12.
RigoF, ChunSJ, NorrisDA, HungG, LeeS, MatsonJ, FeyRA, GausH, HuaY, GrundyJS, KrainerAR, HenrySP and BennettCF. (2014). Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther, 350:46–55.
MillerTM, PestronkA, DavidW, RothsteinJ, SimpsonE, AppelSH, AndresPL, MahoneyK, AllredP, AlexanderK, OstrowLW, SchoenfeldD, MacklinEA, NorrisDA, ManousakisG, CrispM, SmithR, BennettCF, BishopKM and CudkowiczME. (2013). An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol, 12:435–442.
15.
MillerT, CudkowiczM, ShawPJ, AndersenPM, AtassiN, BucelliRC, GengeA, GlassJ, LadhaS, LudolphAL, MaragakisNJ, McDermottCJ, PestronkA, RavitsJ, SalachasF, TrudellR, Van DammeP, ZinmanL, BennettCF, LaneR, SandrockA, RunzH, GrahamD, HoushyarH, McCampbellA, NestorovI, ChangI, McNeillM, FanningL, FradetteS and FergusonTA. (2020). Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med, 383:109–119.
16.
Aartsma-RusA and KriegAM. (2017). FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the Eteplirsen Saga. Nucleic Acid Ther, 27:1–3.
17.
FinkelRS, MercuriE, DarrasBT, ConnollyAM, KuntzNL, KirschnerJ, ChiribogaCA, SaitoK, ServaisL, TizzanoE, TopalogluH, TuliniusM, MontesJ, GlanzmanAM, BishopK, ZhongZJ, GheuensS, BennettCF, SchneiderE, FarwellW, De Vivo; and ENDDC, Study GroupEAR. (2017). Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med, 377:1723–1732.
18.
KorobeynikovVA, LyashchenkoAK, Blanco-RedondoB, Jafar-NejadP and ShneiderNA. (2022). Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med, 28:104–116.
19.
KwonD. (2021). Failure of genetic therapies for Huntington's devastates community. Nature, 593:180.
20.
Estevez-FragaC, RodriguesFB, TabriziSJ and WildEJ. (2022). Huntington's disease clinical trials corner: April 2022. J Huntingtons Dis, 11:105–118.
21.
TabriziSJ, Estevez-FragaC, van Roon-MomWMC, FlowerMD, ScahillRI, WildEJ, Muñoz-SanjuanI, SampaioC, RosserAE and LeavittBR. (2022). Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities. Lancet Neurol, 21:645–658.
