From Johns Hopkins University School of Medicine, Charlotte J. Sumner, M.D., presents an editorial on a study by Richard S. Finkel and colleagues, who report an open-label, Phase II trial of the pre-messenger RNA splicing modifier risdiplam in presymptomatic spinal muscular atrophy.

First described in 1891, spinal muscular atrophy (SMA) is a genetic neuromuscular disease that causes degeneration of spinal and brain-stem motor neurons. Weakness particularly affects proximal limb, respiratory, and pharyngeal skeletal muscles.

With an incidence of approximately one in 10,000 births, SMA is a leading inherited cause of infant death outside developed countries. Without disease-modifying treatment, 60% of persons with SMA have type 1 disease, becoming weak within days or weeks after birth, failing to reach motor milestones, and dying by 2 years of age.

Infants with type 2 SMA become weak at a later stage, usually achieving the ability to sit but not stand. Children with type 3 SMA usually reach the milestone of walking. SMA is caused by recessive loss-of-function variants in SMN1 and reduced expression of the ubiquitously expressed SMN protein.

A paralogous gene, SMN2, is retained in a variable number of copies but cannot fully compensate because a nucleotide variant causes alternative pre-mRNA splicing that excises exon 7 and yields a truncated, rapidly degraded protein.

A small proportion of SMN2 transcripts, once spliced, retain exon 7 and generate full-length, functional SMN protein. Persons with type 1 SMA usually have two SMN2 copies. Persons with type 2 or 3 SMA generally have three or four copies. How SMN deficiency triggers the degeneration of motor neurons remains incompletely understood.

In the editorial, “Presymptomatic Treatment of a Genetic Disease with a Small-Molecule Drug,” published in The New England Journal of Medicine, Sumner shares insights into the Phase II trial and the next steps for countering SMA with risdiplam.

From newborn screening, eight infants with two copies and 18 infants with three or more copies of SMN2 were enrolled in the Phase II design to assess presymptomatic initiation of daily risdiplam. Motor functions and survival were examined with motor milestones reported at 12 and 24 months. Compound muscle action potential amplitudes were measured at baseline.

At 12 months, 96% of the infants could sit unsupported for five seconds and 81% for 30 seconds. At 24 months, of the 23 children still enrolled, 81% could walk alone.

During the study, only six of 26 children had clinically manifested SMA (one was unable to sit and was withdrawn from the study by the caregiver to pursue an alternative treatment, three were unable to walk, and two others were also withdrawn by the caregiver). Each of these children had two copies of SMN2. All three infants with the lowest baseline compound muscle action potential (< 1.5 mV) later had clinical disease.

Risdiplam has broad tissue biodistribution and crosses the blood–brain barrier. It is one of three approved SMN-inducing treatments for SMA. Other approved treatments are nusinersen, the intrathecally administered, splice-switching antisense oligonucleotide, and onasemnogene abeparvovec, the adeno-associated virus 9 gene-transfer therapy.

All three drugs are substantially more effective when started before symptom onset, which has prompted neonatal screening programs for SMA in many countries to hasten treatment initiation.

In the human spinal cord, SMN protein levels are highest during fetal development, which suggests a requirement for SMN during early stages of motor-neuron development. Sufficiently early SMA treatment probably not only halts irreversible neurodegeneration but also facilitates normal motor-neuron and muscle development.

Further efforts to characterize the long-term outcomes of single treatments and effects of sequential or combined treatments are needed. Many infants with SMA and two copies of SMN2 continue to have clinical deficits despite neonatal treatment.

As the first successful, gene-specific RNA-processing drug, risdiplam has provided proof of concept that a small-molecule drug can safely and effectively target an mRNA. Efforts are ongoing to develop other RNA-targeting small molecules that may be safe and effective for treating other diseases.

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