How far away is spinal muscular atrophy gene therapy?

Abstract

Spinal muscular atrophy (SMA) is a devastating motor neuron disease primarily affecting children, for which there is currently no known disease-modifying therapy or cure. The identification of the disease gene, survival motor neuron, led to an expansion in SMA research and allowed the creation of numerous animal and cellular models. This led to a significant increase in our understanding of the pathophysiology of SMA, culminating in the development of multiple SMN-dependent and -independent therapies. Among the most exciting options, viral gene therapy has emerged as one leading candidate. A growing body of pre-clinical evidence suggests that administration of scAAV9 carrying an SMN transgene can be both efficacious and translationally viable. In this article, we briefly review the progress which has been made in the field, and provide a commentary on some of the challenges which remain.

Keywords:

• AAV9
• delivery route
• gene therapy
• SMN
• spinal muscular atrophy
• therapeutic time window

Financial & competing interests disclosure

TH Gillingwater is supported by grants from the SMA Trust, Muscular Dystrophy UK, and the AxonomiX Network. LM Murray is supported by grants from the Muscular Dystrophy Association, Fight SMA, Cure SMA and the Gwendolyn Strong Foundation. The authors have no other 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 apart from those disclosed.

Key issues

• Spinal muscular atrophy (SMA) is a monogenetic childhood motor neuron disease for which there is no know treatment or cure.

• Recent work has revealed that intravenous delivery of scAAV9 carrying a transgene for SMN can dramatically rescue severe mouse models of SMA.

• Work in pig and primates has proven scAAV9 can cross the blood–brain barrier following intravenous injection, and can express an exogenous protein in their motor neurons.

• Phase I clinical trials using scAAV9 in SMA patients are currently underway.

• It is still unclear which tissues we need to target for SMN replacement therapy.

• It is likely SMN replacement therapies will have to be given prior to symptom onset for maximum benefit.

• The results of the current clinical trials will be directive to future trials using viral vectors in SMA patients.