Abstract and Introduction
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's 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.
Many neurogenetic disorders are of monogenic origin. In these diseases, the abnormal DNA sequence will lead to the production of an abnormal protein, not or incompletely functioning (loss of function mechanism) or with a toxic gain of function. The abnormal RNA transcript itself may also have a toxicity. The objective with gene-centred approaches is to act specifically on the abnormal gene product by targeting an intermediate step from the gene to the protein. Among these approaches, antisense therapies target the RNA transcript, mostly pre-messenger or mature messenger RNA, and result in post-transcriptional gene silencing. Contrary to more 'classical' therapeutic molecules, complementary base pairing to RNA is at the root of antisense therapies and allows for a—theoretically—specific targeting of the pathogenic RNA transcript implicated in the disease, in specific cells and tissues expressing this gene. In addition, there is no modification of the genome in the targeted cells as compared with the genome editing approaches. This leads to fewer concerns regarding neoplastic adverse events and regarding irreversible modifications of the genome. Intrathecal or intracerebral administrations can overcome the blood–brain barrier issue for delivery of the treatment; intravenous administration is able to deliver RNAi therapeutics in the liver for hereditary monogenic diseases of the liver with neurological manifestations (transthyretin-related hereditary amyloidosis and acute hepatic porphyria) and in the muscles for myopathies such as Duchenne muscular dystrophy. The lack of integration in the genome can also be viewed as a drawback, as repeated administrations may be necessary. We present in this review the current neurological applications or development of antisense therapies in various neurological disorders at different stages of development.
Brain. 2022;145(3):816-831. © 2022 Oxford University Press