Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Abstract

RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. Abbreviations 2’-MOE: 2’- O -(2-methoxyethyl); 2’- O -Me: 2’- O -methyl; 2’-F: 2’-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

“…As few examples, other more specific strategies, such as gene and cell therapies are promising approaches for these diseases [ 302 , 303 , 304 ]. These approaches rely on the use of stem cells and of vectors conceived on the bases of the recently approved gene therapies adopted for SMA [ 305 ], as well as on the use of synthetic antisense oligonucleotides specifically targeting the mRNA transcript encoding the mutant protein responsible for a given MND [ 306 , 307 , 308 , 309 , 310 ]. The present limitation of their use is the capability to deliver the various vectors or nucleotides in the affected tissues in order to be taken up from cells involved in the disease.…”

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington’s Disease

“…Clinical studies on repurposing old drugs to manage HD are currently underway. Several reviews on therapeutics for HD in clinical trials, drug repurposing, or other therapies, such as ASOs, siRNA, and CRISPR, have recently been published. − For instance, Bharate and co-workers elegantly and comprehensively reviewed small molecules under clinical trials . However, they did not include any preclinical candidates and solely described the clinical pipeline of anti-HD small molecules .…”

Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia

“…The currently RNAi drugs only include N-acetylgalactosamine-siRNA conjugates (givosiran, inclisiran, and lumasiran), which targets to hepatocyte and siRNA drugs (vutrisiran and onpattro) that can treat the familial amyloid polyneuropathy ( Kulkarni et al, 2021 ; Holm et al, 2022 ). Although RNAi shows the different ways of gene silencing in each ND, it seems to be a general treatment for them.…”