Gene-Targeting Therapeutics for Neurological Disease: Lessons Learned from Spinal Muscular Atrophy

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.

Automated summary

In recent decades, there has been significant progress in identifying the genes causing monogenetic neurological diseases and developing gene-targeting therapeutics, leading to increased tractability of once incurable neurological conditions. Spinal muscular atrophy (SMA), historically a leading inherited cause of infant mortality, has seen approval of three treatments by the US FDA in the last 5 years, reflecting remarkable advancements in the field. Despite this progress, understanding drug pharmacokinetics, target engagement in neurons, potential toxicities, and long-term effects remains crucial for further therapeutic optimization.