Spinal muscular atrophy therapeutics development

Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Overview
SMA disease severity has been found to be inversely related to the number of SMN2 gene and the amount of SMN protein present. Efforts are being directed to develop agents that can increase the amount of SMN2 gene and the SMN proteins. Also, other approaches like stem cell therapy, gene therapy are active areas of research. There is no standard treatment of SMA till date. However, the recent developments in molecular genetics have helped in understanding the pathogenesis of the disease and raises hope for a future treatment. Below are the drugs that have been actively studied in animal models and various clinical trials.

Drugs that act by increasing SMN protein, number of SMN2 gene, number of nuclear gems

Histone deacetylase inhibitors.


 * 'Phenylbutyrate'


 * 'Valproic acid' - already widely used in treatment of Epilepsy


 * 'LBH589 (hydroxamic acid)', already widely used in cancer clinical trials

Non-histone deacetylase inhibitors, but that also affect SMN2 gene expression levels or promote inclusion of exon 7 are-


 * 'Albuterol', a beta-adrenergic agonist already widely used in treatment of Asthma.


 * 'Indoprofen' is a Non-steroidal anti-inflammatory drug.

Other approaches-


 * 'Aminoglycosides' appear to promote read-through of the stop codon and thereby stabilize the SMN protein.


 * 'Riluzole and Gabapentin'


 * 'NMDA receptor activation'


 * 'Antisense oligonucleotides' (ASO) have been shown to prevent skipping of exon 7, that in turn enhances production of full-length SMN mRNA in fibroblasts from patients


 * 'Stem cells therapy' - Pluripotent stem cells with the capacity to differentiate into motor neurons could serve as an important model system.


 * 'Gene therapy'