A Chemical Biology Perspective to Therapeutic Regulation of RNA Splicing in Spinal Muscular Atrophy (SMA)

Abstract

Manipulation of RNA splicing machinery has emerged as a drug modality. Here, we illustrate the potential of this novel paradigm to correct aberrant splicing events focused on the recent therapeutic advances in spinal muscular atrophy (SMA). SMA is an incurable neuromuscular disorder and at present the primary genetic cause of early infant death. This Review summarizes the exciting journey from the first reported SMA cases to the currently approved splicing-switching treatments, i.e., antisense oligonucleotides and small-molecule modifiers. We emphasize both chemical structures and molecular bases for recognition. We briefly discuss the advantages and disadvantages of these treatments and include the remaining challenges and future directions. Finally, we also predict that these success stories will contribute to further therapies for human diseases by RNA-splicing control.

Reversible Control of RNA Splicing by Photoswitchable Small Molecules

“…Inspired by the approval of the oral splicing modifier risdiplam ( 1 , commercialized under the name Evrysdi, Figure A) for the treatment of spinal muscular atrophy (SMA) in 2020, we envisioned exerting light-controllable manipulation in RNA splicing to modulate survival motor neuron (SMN) protein levels, which is the molecular target of SMA. SMA is an incurable neuromuscular disease where the C-to-U transition on exon 7 of the gene SMN2 causes exon skipping and, consequently, an aberrant variant . Less than 10 years ago, different laboratories reported small molecules capable of specifically including 7 exon and restoring the healthy levels of SMN.…”

“…SMA is an incurable neuromuscular disease where the C-to-U transition on exon 7 of the gene SMN2 causes exon skipping and, consequently, an aberrant variant. 37 Less than 10 years ago, different laboratories reported small molecules capable of specifically including 7 exon and restoring the healthy levels of SMN. In particular, the derivatives 2 38 and 3 39 called our attention (Figure 1A).…”

Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities

“…It was hypothesized that, to address the lack of SMN levels, increasing inclusion of exon 7 would lead to higher levels of full-length transcript and, consequently, more SMN2 protein, which would modify the course of SMA. In this context, the development of branaplam and risdiplam as small molecules that can selectively increase exon 7 inclusion has led to a new therapeutic modality: selective splice modulation …”

“…In this context, the development of branaplam and risdiplam as small molecules that can selectively increase exon 7 inclusion has led to a new therapeutic modality: selective splice modulation. 23 Since SMA is caused by an aberration in protein quantity, rather than protein function, the pursuit of small molecule therapeutics for SMA presented the significant challenge of identifying a small molecule that could affect protein levels. There was knowledge of the genetic basis of SMA and a measurable cellular phenotype, i.e., increased levels of SMN2, that had a strong connection to the molecular pathogenesis of SMA.…”

Phosphorylation mediated regulation of RNA splicing in plants

“…In human cells, AS regulates essential functions such as autophagy ( Paronetto et al., 2016 ; Lv et al., 2021 ), apoptosis ( Singh et al., 2016 ; Kędzierska and Piekiełko-Witkowska, 2017 ; Stevens and Oltean, 2019 ), protein localization ( Link et al., 2016 ), and transcription factor activity ( Chen et al., 2022 ), amongst others ( Baralle and Giudice, 2017 ). Therefore, it is no surprise that AS dysregulation results in several medical conditions including: cancer ( Da Silva et al., 2015 ; Wang et al., 2016 ), heart disease ( Liu et al., 2019 ; Hasimbegovic et al., 2021 ), neurological disorders ( Low et al., 2021 ; Zhang et al., 2022 ; Nishanth and Jha, 2023 ) and multiple genetic disorders ( Maule et al., 2019 ; Ajiro et al., 2021 ; Jiang and Chen, 2021 ). Hence in humans, PTM regulation and the signaling pathways governing AS, have been extensively studied, offering opportunities for comparative analysis of new findings being made in plants.…”