The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.
Keywords: antisense oligonucleotide; biomarkers; gene therapy; small molecules; spinal muscular atrophy.