Spinal Muscular Atrophy (SMA): Treatment strategies, challenges and future prospects

Abstract

Introduction

Spinal muscular atrophy (SMA) is a pediatric neuromuscular disorder that is distinguished by a defect or mutation in the survival motor neuron1 (SMN1) gene. It is a profoundly impactful childhood motor neuron disorder. In its most severe instances and in the absence of treatment, it tragically results in death within the initial two years of life. The disease is identified by muscle weakness and atrophy, predominating in proximal limb muscles. The most common mutation causing SMA is a homozygous deletion of exon 7 of SMN1. Recent therapeutic breakthroughs provide hope to families and patients by tackling the deficiency in SMN protein using gene therapy or alternative genetic manipulation techniques. It is becoming increasingly clear that none of these therapies alone will provide a cure for SMA. Therefore, the objective of the study is to review the correlation between SMN protein levels in tissues and the pathology of SMA. It also aims to provide a comprehensive review of the three currently licensed therapies for SMA, offering a brief overview of their preclinical and clinical studies that led to marketing authorization, coupled with real-world data analysis. Additionally, the study delves into discussions surrounding combined therapy, supplementary therapeutic approaches, challenges in clinical care, and future prospects for the treatment of SMA.

Materials and methods

The data for this study were gathered from a range of scholarly sources, including PubMed, Scopus, Springer and other relevant search engines. These sources were selected to ensure access to the latest and most comprehensive literature on SMA management, reflecting current treatment paradigms and advancements in the field.

Results

Both preclinical and clinical investigations of risdiplam, onasemnogene abeparvovec, and nusinersen have elucidated the restoration of functional SMN protein and its distribution in both peripheral tissues and central nervous system (CNS) motor neurons, representing a promising therapeutic benefit for the treatment of SMA.

Discussion

Clinical trials and real-world data provide robust support for the efficacy and safety profiles of the available drugs. Three therapies, nusinersen, onasemnogene abeparvovec, and risdiplam, aim to increase SMN levels in patients with SMA. Currently, an improvements in safety, efficacy, and motor function have been observed in combination therapies, such as the TOPAZ study (Nusinersen with Aptiegromab), the RESPOND study (Nusinersen with Onasemnogene abeparvovec) and the SAPPHIRE study (Aptiegromab alongside nusinersen or risdiplam).