We reviewed the current antisense therapies in various neurological diseases, which show great promise, but many unknowns remain. The most advanced ones are already in use or currently at the clinical stage of development, either at the phase 3 or market authorization stage, such as in spinal muscular atrophy, transthyretin-related hereditary amyloidosis, Duchenne muscular dystrophy, porphyria and amyotrophic lateral sclerosis, for instance; or in earlier clinical phase 1 B, for Huntington disease, synucleinopathies and tauopathies. Other antisense therapies are at the preclinical stage of development such as in other tauopathies and spinocerebellar ataxias, or under development in other various rare neurological disorders including paediatric developmental disorders, neurovascular disorders, myopathies, etc. Many more are also at a preclinical stage, as the scope of neurological diseases amenable to antisense treatments is broadening on a daily basis. Each subtype of antisense therapies, ASO or iRNA, proved its target engagement or even its clinical efficacy in patients. They are undisputable recent advances for severe and previously untreatable neurological disorders. Improving the ASO addressing its CNS target will be of importance. Main achievements mostly concern orphan or rare diseases and expanding this approach to premanifest carriers in genetic disorders or sporadic widespread neurodegenerative disorders is still under development and remains one of the next critical challenges, in particular regarding the recent critical short- and long-term safety issues currently under discussion. There is a knowledge gap regarding the long-term efficacy and toxicity of these new emerging treatments. Apart from the technical, safety and scientific aspects, cost–effectiveness study will be necessary as the yearly price will make these life-saving therapies unaffordable for many families or worldwide healthcare systems, raising ethical issues.
20-MOE = 20-O-methoxyethyl; AAV = adeno-associated virus; ASO = antisense oligonucleotides; ATTR = amyloid TTR; EMA = European Medicine Agency; FDA = US Food and Drugs Administration; mNIS + 7 = modified Neuropathy Impairment Score + 7; PN = phosphoramidate modification; PS = phosphorothioate modification; RISC = RNA-induced silencing complex; SNP = single nucleotide polymorphism
No funding was received towards this work.
None of the authors has any competing interests in the current work. Outside the submitted work: J.B.B.d.C. is a shareholder in Sanofi. D.A. has served in advisory boards for Alnylam and Pfizer, has received speech honoraria from LFB, Alnylam. L.L.M. has received research support grants from INSERM, JNLF, The L'Oreal Foundation; speech honoraria from CSL, Sanofi-Genzyme, Lundbeck, Teva; consultant for Alzprotect, Accure, Digitsole and received travel funding from the Movement Disorders Society, ANAINF, Merck, Merz, Medtronic, Teva and AbbVie. J.-C.C. has served on advisory boards for Air Liquide, Biogen, Denali, Ever Pharma, Idorsia, Prevail Therapeutic, Theranexus, UCB; and received grants from Sanofi and the Michael J Fox Foundation, outside the submitted work. A.D. is currently receiving grants from the National Institute of Health (RO1), French National Hospital Clinical Research Program (PHRC), Agence National de Recherche (ANR), Triplet Therapeutics, Biogen, Minoryx Therapeutics, Roche and Verum. A.D. serves on the advisory boards of Triplet Therapeutics and Minoryx Therapeutics. She holds partly a Patent B 06291873.5 'Anaplerotic therapy of Huntington's disease and other polyglutamine diseases'.
Brain. 2022;145(3):816-831. © 2022 Oxford University Press