Antisense therapies in neurological diseases

Abstract

Advances in targeted regulation of gene expression allowed new therapeutic approaches for monogenic neurological diseases. Molecular diagnosis has paved the way to personalized medicine targeting the pathogenic roots: DNA or its RNA transcript. These antisense therapies rely on modified nucleotides sequences (single-strand DNA or RNA, both belonging to the antisense oligonucleotides family, or double-strand interfering RNA) to act specifically on pathogenic target nucleic acids, thanks to complementary base pairing. Depending on the type of molecule, chemical modifications and target, base pairing will lead alternatively to splicing modifications of primary transcript RNA or transient messenger RNA degradation or non-translation. The key to success for neurodegenerative diseases also depends on the ability to reach target cells. The most advanced antisense therapies under development in neurological disorders are presented here, at the clinical stage of development, either at phase 3 or market authorization stage, such as in spinal amyotrophy, Duchenne muscular dystrophy, transthyretin-related hereditary amyloidosis, porphyria and amyotrophic lateral sclerosis; or in earlier clinical phase 1 B, for Huntington disease, synucleinopathies and tauopathies. We also discuss antisense therapies at the preclinical stage, such as in some tauopathies, spinocerebellar ataxias or other rare neurological disorders. Each subtype of antisense therapy, antisense oligonucleotides or interfering RNA, has proved target engagement or even clinical efficacy in patients; undisputable recent advances for severe and previously untreatable neurological disorders. Antisense therapies show great promise, but many unknowns remain. Expanding the initial successes achieved in orphan or rare diseases to other disorders will be the next challenge, as shown by the recent failure in Huntington disease or due to long-term preclinical toxicity in multiple system atrophy and cystic fibrosis. This will be critical in the perspective of new planned applications to premanifest mutation carriers, or other non-genetic degenerative disorders such as multiple system atrophy or Parkinson disease.

Phenotypic complexities of rare heterozygous neurexin-1 deletions

“…We find that ASOs designed to target the mutant splice junction and facilitate degradation of mutant isoforms provides a therapeutic approach to ameliorate the toxic effects of GOF mutations. While gene therapy in brain disease has resulted in mixed successes ( 36 ), cases of muscular dystrophies which have been treated via splicing modulating ASOs have proved effective ( 37 ). For LOF mutations, mechanisms for upregulating wild-type allele are needed.…”

“…6e ). While gene therapy in brain disease has resulted in mixed successes 38 , cases of muscular dystrophies which have been treated via splicing modulating ASOs have proved effective 39 .…”

Current potential therapeutics of amyotrophic lateral sclerosis

“…Approximately 2% of patients with ALS have mutations in the gene that encodes SOD1 , a metalloprotease that protects against oxidative stress. These mutations lead to the dysregulation and overproduction of SOD1 protein ( 3 , 57 , 58 ). Under development by Biogen, Tofersen, known commercially as Qalsody™, is a therapeutic antisense oligonucleotide designed to target SOD1 mRNA, with the goal of treating ALS.…”

A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

“…Splice-switching AOs are short synthetic, chemically modified nucleic acid molecules, typically 15–30 residues in length, that are capable of complementary binding to mRNA thereby altering splice site selection [ 17 , 18 ]. Several splice-switching AOs have been successfully developed for the treatment of fatal muscle-wasting disorders, Duchenne muscular dystrophy (DMD) and spinal muscular atrophy [ 19 , 20 ]. Three drugs were granted accelerated approval by the Food and Drug Administration in 2016 and later in 2019 and 2021 for skipping DMD exon 51 ( Exondys51 or Eteplirsen ) [ 21 ], exon 53 ( Vyondys53 or Golodirsen ) [ 22 ], and exon 45 ( Amondys45 or Casimersen ) [ 23 , 24 ], respectively.…”