Advances and challenges in developing a therapy for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a debilitating and incurable childhood onset disease characterized by the degeneration of motor neurons in the spinal cord resulting in muscular atrophy and paralysis. Over the past 20 years, there has been significant progress in understanding the molecular basis of the disease, allowing researchers to identify the main causative gene and successfully model SMA in various animals. Despite an improved understanding of the disease, there is still no effective treatment for SMA patients. Here, we discuss the current knowledge surrounding the pathogenesis of SMA, and outline recent advances toward the development of a successful therapy for this devastating disease.

Keywords:

• AAV
• antisense
• spinal muscular atrophy
• survival motor neuron
• treatment

Acknowledgements

The authors thank Li Shan Chiu for assistance with anatomical illustrations.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Key issues

• The survival of motor neuron (SMN) protein is an essential developmental and survival protein for motor neurons.

• A successful spinal muscular atrophy (SMA) treatment will require early administration, and will likely involve systemic SMN restoration to alleviate involvement of other non-neural tissues.

• Despite improvements and the rescue of SMA animal models by a range of chemical compounds, clinical trials to date reveal a significant lack of translation.

• Antisense oligonucleotide-mediated targeting of SMN2 significantly improves exon 7 inclusion and survival in mouse SMA models.

• Promising Phase I and Phase II clinical trial results show the feasibility of antisense-mediated SMN restoration, however, the efficacy of this approach and whether improved functional motor outcomes can be achieved is yet to be determined.

• Gene therapy using an AAV vector ameliorates the disease phenotype in SMAΔ7 mice and clinical trials using the AAV9 vector are currently recruiting patients.

Notes