Prenatal SMA treatment improves outcomes but may need to continue
Treatment before birth with RG7916, a compound similar to Evrysdi (risdiplam), improved weight, muscle health, motor function, and survival in a mouse model of severe spinal muscular atrophy (SMA), a study found.
However, treatment given only before birth, or prenatally, did not fully preserve numbers of motor neurons — the specialized nerve cells progressively lost in SMA. The findings suggest prenatal therapy alone may not be enough.
“Our efforts demonstrate a combination of prenatal and postnatal [after-birth] therapy must be used for optimum therapeutic outcomes in the treatment of patients with SMA,” the researchers wrote.
Study tests prenatal treatment in severe SMA mice
The study, “Maternal-Fetal Administration of Risdiplam Partially Rescues the SMNΔ7 Mouse Model of Spinal Muscular Atrophy,” was published in Annals of Neurology.
SMA is caused by mutations in the SMN1 gene, leading to low levels of SMN, a protein essential for the health of motor neurons, which control movement. When these nerve cells degenerate, muscles weaken and waste away.
Available disease-modifying therapies, including Evrysdi, have greatly improved outcomes for many people with SMA, especially when started before symptoms appear, known as the presymptomatic stage. However, these therapies are approved for use only after birth.
Evidence suggests SMA-related damage can begin during fetal development, particularly in babies with severe disease, who tend to have fewer copies of SMN2. SMN2 is a backup gene that can produce some SMN protein, but each copy makes only a small amount of the functional, full-length protein.
Researchers therefore wanted to determine whether treatment during fetal development could provide benefits beyond treatment started only after birth. A team in Canada evaluated prenatal exposure to RG7916, which the study described as a risdiplam-like compound, in a mouse model of severe SMA.
Mice in this model begin showing weakness at about 4 days of age and live an average of about 13 days without treatment.
Pregnant mice were given either RG7916 or an inactive control mixture, delivered directly into the stomach. Treatment started midway through gestation and continued daily for 10 days, from embryonic day 9.5 through day 19.5. No treatment was given after birth. The researchers then monitored the pregnant mice and their offspring.
Prenatal exposure to RG7916 significantly improved weight, motor function, measures of muscle health, and survival in SMA mice, which also appeared healthier than mice given the inactive mixture.
Movement and muscle health improve with treatment
Motor function was assessed using the righting reflex, a test that measures how quickly a mouse placed on its back can turn over. From the earliest assessment at 5 days of age, prenatally treated SMA mice turned over significantly faster, with performance comparable to that of healthy littermates.
Prenatal RG7916 treatment significantly increased the size of muscle fibers in the tibialis anterior, a lower-leg muscle, and reduced the number of centrally located nuclei, a sign of ongoing muscle repair or immature muscle fibers. There were also signs of improved health at neuromuscular junctions, where nerves communicate with muscles.
Survival also was significantly improved. SMA mice exposed to RG7916 before birth lived more than 2.5 times as long as mice given the inactive mixture.
However, treated SMA mice stopped gaining weight after postnatal day 15, and survival declined sharply after day 36. According to the researchers, this likely reflected the return of disease-related problems because treatment was not continued after birth.
At postnatal day 13, prenatal RG7916 treatment was associated with increased SMN protein levels in the spinal cord and skeletal muscle, but SMN levels were not maintained in the brain.
Also, motor neuron numbers were not fully maintained in the spinal cord at postnatal day 13. Despite this, the size of motor neuron cell bodies was rescued at postnatal day 13, suggesting some benefit to motor neuron health.
Motor neuron benefits were not fully maintained
These findings suggest that “motor neurons may have been rescued prenatally yet degenerate post-birth because of the lack of continued postnatal treatment,” the researchers wrote.
Researchers found no signs of liver injury in the pregnant mice, and measured immune and inflammatory markers were consistent with control levels five weeks after birth. However, they noted potential safety concerns: three of the 10 treated pregnancies did not reach term, pregnancies were shorter, and stillbirths were more common in the treated group.
The team also noted that the dose used in the study was high and that more research is needed to understand possible toxicity.
Overall, these findings “support the concept that intervention during early development may improve disease outcomes in SMA,” the researchers wrote. However, further studies are needed to determine safe dosing and timing and to evaluate risks to both the mother and fetus before prenatal treatment strategies could be considered in people.
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