Gene– and nucleic acid–based therapeutics for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a lower motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein due to deletions or mutations in the SMN1 gene. In SMA patients, SMN protein is produced from the paralogous gene SMN2, but the produced amount of SMN is minimal due to a defect in the splicing process. Nusinersen, an antisense oligonucleotides, and risdiplam, an oral small molecule, have been developed to repair SMN2 splicing failure for full amount of SMN production. Nusinersen has been used in clinical practice in these years and the improvement of clinical score has been observed even in adult patients with long disease duration. Thus, it has led to a dramatic evolution for SMA treatment. Risdiplam has the advantage of oral administration and the accumulation of real–world data on its efficacy in adult patients is now ongoing. In addition, onasemnogene abeparvovec utilizes a nonreplicating adeno–associated virus 9 to provide a copy of the gene encoding the SMN protein and is applicable for patients younger than 2 years of age. Onasemnogene has significantly improved the prognosis of severe cases with SMA. Since these drugs are extremely costly and their treatment responses differ between individuals, discontinuation or replacement with another drug should be considered if they are truly ineffective. However, it is not always easy to determine the efficacy of treatment by clinical scores, especially in adult patients with slow progression of the disease. Therefore, the development of reliable biomarkers is underway that can objectively help to evaluate the treatment efficacy. In addition to the molecular markers such as neurofilament H, creatinine, and cathepsin D, microRNA is attracting attention. SMA therapy is a representative example of a successful treatment for neurodegenerative diseases and is expected to have a major impact on the development of future treatments for many intractable neurological diseases.