Diving into progress: a review on current therapeutic advancements in spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is an uncommon disorder associated with genes characterized by the gradual weakening and deterioration of muscles, often leading to substantial disability and premature mortality. Over the past decade, remarkable strides have been made in the field of SMA therapeutics, revolutionizing the landscape of patient care. One pivotal advancement is the development of gene-targeted therapies, such as nusinersen, onasemnogene abeparvovec and risdiplam which have demonstrated unprecedented efficacy in slowing disease progression. These therapies aim to address the root cause of SMA by targeting the survival motor neuron (SMN) gene, effectively restoring deficient SMN protein levels. The advent of these innovative approaches has transformed the prognosis for many SMA patients, offering a glimmer of hope where there was once limited therapeutic recourse. Furthermore, the emergence of small molecule compounds and RNA-targeting strategies has expanded the therapeutic arsenal against SMA. These novel interventions exhibit diverse mechanisms of action, including SMN protein stabilization and modulation of RNA splicing, showcasing the multifaceted nature of SMA treatment research. Collective efforts of pharmaceutical industries, research centers, and patient advocacy groups have played an important role in expediting the translation of scientific discoveries into visible clinical benefits. This review not only highlights the remarkable progress achieved in SMA therapeutics but also generates the ray of hope for the ongoing efforts required to enhance accessibility, optimize treatment strategies, rehabilitation (care and therapies) and ultimately pave the way for an improved quality of life for individuals affected by SMA.

Keywords: nusinersen; onasemnogene abeparvovec; rehabilitation; risdiplam; spinal muscular atrophy; survival motor neuron.

Figure 1

Comprehensive insight into the progression of SMA. The top panel categorizes the five types of SMA (0, 1, 2, 3, 4) which is based on the onset age and achieved motor capabilities. SMA type 3 is further subdivided upto 3a (onset <3 years) and 3b (onset >3 years). Furthermore, the figure presents the total count of SMN2 gene copies for each SMA type.

Figure 2

Human survival motor neuron (SMN) gene expression is shown in a schematic diagram for both healthy people and those with SMA. The chromosome 5q13 region (long arm of chromosome 5) has been explicitly identified as the location of the telomeric SMN1 and centromeric SMN2 genes. Full-length, functional SMN (FL-SMN) protein is produced by the SMN1 gene whereas the SMN2 gene, owing to incorrect splicing, produces 90% truncated SMN protein (SMNΔ7) and only 10% of FL-SMN protein. (A) Both SMN genes are present in healthy individuals. (B) The SMN1 gene is absent in SMA patients due to mutations, which prevent SMN1 from producing FL-SMN protein (this condition is denoted by a red “X”). Because production is completely dependent on the SMN2 gene, there is inadequate production.

Figure 3

Supportive care and multidisciplinary approach flow chart.