Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and one of the most common genetic causes of infant death. It is characterized by progressive weakness of the muscles, loss of ambulation, and death from respiratory complications. SMA is caused by the homozygous deletion or mutations in the survival of the motor neuron 1 (SMN1) gene. Humans, however, have a nearly identical copy of SMN1 known as the SMN2 gene. The severity of the disease correlates inversely with the number of SMN2 copies present. SMN2 cannot completely compensate for the loss of SMN1 in SMA patients because it can produce only a fraction of functional SMN protein. SMN protein is ubiquitously expressed in the body and has a variety of roles ranging from assembling the spliceosomal machinery, autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Motor neurons in the anterior horn of the spinal cord are extremely susceptible to the loss of SMN protein, with the reason still being unclear. Due to the ability of the SMN2 gene to produce small amounts of functional SMN, two FDA-approved treatment strategies, including an antisense oligonucleotide (AON) nusinersen and small-molecule risdiplam, target SMN2 to produce more functional SMN. On the other hand, Onasemnogene abeparvovec (brand name Zolgensma) is an FDA-approved adeno-associated vector 9-mediated gene replacement therapy that can deliver a copy of the human SMN1. In this review, we summarize the SMA etiology, the role of SMN, and discuss the challenges of the therapies that are approved for SMA treatment.
Highlights
Proximal spinal muscular atrophy (SMA) is one of the most commonly inherited genetic disorders with a prevalence of 1/11,000 births and a carrier frequency of 1/40 to 1/60 [1]
SMA is caused by mutations in the survival of motor neuron 1 gene (SMN1), which is majorly involved in the proper functioning of the motor neurons by assisting the assembly of small nuclear ribonucleoprotein complexes [5]
Despite the varying phenotypes and severity seen in SMA patients, the causal genetic factor has been localized to the same locus chromosome 5q11.2–13.3, which led to the identification of the SMN1 gene as the SMA-causing gene in 1994 by Melki and colleagues [17,18]
Summary
Proximal spinal muscular atrophy (SMA) is one of the most commonly inherited genetic disorders with a prevalence of 1/11,000 births and a carrier frequency of 1/40 to 1/60 [1]. There are three approved treatments by the Food and Drug Administration (FDA) that are directed towards increasing the production of SMN protein. Viral-vector-based gene therapy (Zolgensma, onasemnogene abeparvovec-xioi) for SMA was approved by the FDA in 2019 to deliver a functional copy of the SMN cDNA as a one-time intravenous administration to patients below the age of 2 years [12]. The third approved drug is known as risdiplam (brand name Evrysdi) developed by Roche, PTC Therapeutics Inc. and the SMA Foundation [13] It is an orally available SMN2-directed RNA splicing modifier that received its approval in August 2020 for patients 2 months and older. We shall provide insights into alternative treatment strategies that are currently being studied to ameliorate the disease phenotype
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