Drug Discovery of Spinal Muscular Atrophy (SMA) from the Computational Perspective: A Comprehensive Review

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.

Prospective Analysis of Functional and Structural Changes in Patients with Spinal Muscular Atrophy—A Pilot Study

“…Type 1 (SMA1; Werdnig-Hoffmann) applies to patients who never achieve the function of sitting up on their own, with the onset of symptoms occurring in the first few months of life. Type 2 (SMA2) are sedentary patients with a diagnosis between 6 and 18 months of age, who will never achieve independent walking, while mild type 3 (SMA3; Kugelberg-Welander) applies to children whose highest function is independent walking, and the onset of symptoms occurs after 18 months of age [ 4 , 7 , 9 ].…”

“…Furthermore, some children are participating in gene therapy with the help of private funding. Zolgensma (Onasemnogene abeparvovec) uses adenovirus serotype 9 (AAV9), which is a vector to deliver a synthetic DNA sequence corresponding to the SMN1 gene to motor neurons, resulting in the formation of the missing SMN protein [ 9 , 10 , 14 ]. From 1 September 2022, reimbursement of all these drugs was introduced in Poland.…”

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

“…SMA symptoms exists on a spectrum and patients are classified in five stratifications (SMA Type 0 – 4) which guide clinical care 2,4 . These groups are determined based on the degree of motor symptom involvement and the age of onset.…”

History of development of the life-saving drug “Nusinersen” in spinal muscular atrophy

“…The advent of Spinraza (nusinersen) represents an effective treatment approach, and it became the first drug to be approved for SMA by the U.S. Food and Drug Administration (FDA). Subsequently, two more drugs, Zolgensma (onasemnogene abeparvovecxioi) and Evrysdi TM (risdiplam) were approved by the FDA in 2019 and 2020, respectively, and multiple R&D pipelines are in the clinical stage, providing further encouragement in the search of a complete cure for SMA (Chong et al, 2021). Nusinersen is the first widely used SMA drug and is known for its excellent efficacy.…”