Abstract
Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.
Highlights
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease (NMD), arising from loss-of-function mutations of survival motor neuron 1 (SMN1) gene
RG7916, is an investigative drug being developed by Hoffmann-La Roche in collaboration with PTC Therapeutics and SMA Foundation to treat all types of SMA [62]
A network analysis based on the two main proteins (Figure 7), SMN1 and SMN2, as protein input in GeneMANIA (https://genemania.org/) [223], has generated a network of putative interacting proteins that works in unison to bring about the phenotypes as seen in SMA
Summary
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease (NMD), arising from loss-of-function mutations of survival motor neuron 1 (SMN1) gene. It is one of the leading inherited causes of infant and early childhood mortality [1,2]. SMA is the leading genetic cause of infant mortality globally [17,18] and the second most common fatal autosomal recessive disorder after cystic fibrosis [19,20] It occurs with an estimated pan ethnic incidence of 1 in 6000–10,000 live births and a carrier frequency of 1 in 40–60 [21,22,23]. SMA patients can be classified into five clinical types based on age of onset and level of motor function [32]
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