Levels of the survival motor neuron (SMN) protein — which are significantly low in spinal muscular atrophy (SMA) patients — naturally rise during gestation and then fall in the three months before and after birth, highlighting a critical window for treating SMA that runs up to the first three months of life, a study reports.
These findings reinforce clinical trial data showing that early treatment with current therapies — treatment given as soon as possible — leads to the best results, and support newborn screening programs for SMA.
Researchers also report that Spinraza (nusinersen) appears to have limited distribution to anterior spinal regions (those closest to body organs) and the brain, possibly because of its inability to cross the brain-blood barrier and its current set 12 mg (5mL) dose for all patients.
The study, “Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment,” was published in The Journal of Clinical Investigation.
SMA is caused by mutations in the SMN1 gene that leads to low or no SMN protein production, a protein essential for muscle health. A second survival motor neuron gene (SMN2), with an identical sequence, only partly compensates for the loss of SMN1-produced SMN.
Current approved SMA therapies include Spinraza — an antisense oligonucleotide (ASO) that increases the ability of the SMN2 gene to produce a functional SMN protein — and Zolgensma, a gene therapy (marketed by Novartis) that brings the healthy SMN1 gene to a patient’s cells.
Several preclinical and clinical studies have shown that the range of these medicines’ therapeutic effects depends on a patient’s age at the start of treatment, with earlier starts inducing greater benefits.
But the reasons for this are not fully understood, and little is known about the natural, disease- and treatment-associated temporal dynamics of SMN levels in disease-affected tissues.
Researchers at Johns Hopkins School of Medicine and collaborators — which include eight employees of Ionis Pharmaceuticals or PTC Therapeutics among its 22 scientists — evaluated the levels of SMN protein and messenger RNA (mRNA) in tissues collected shortly after death from both unaffected people and SMA patients of different ages. mRNA is the intermediate molecule produced from DNA, which holds the instructions to produce a protein.
The work was funded by the SMA Foundation, spinal muscular atrophy research team (SMART), National Institutes of Health (NIH), as well as Ionis and PTC. Biogen, which developed and markets Spinraza, also provided financial support for specific aspects of the study.
Researchers analyzed disease-relevant tissues (from the brain, spinal cord, a hip flexor muscle, and the diaphragm) from 13 unaffected people and 27 SMA patients (including five treated with Spinraza) at John Hopkins, and 115 unaffected people from the NIH NeuroBioBank. Their ages ranged from 15 weeks of gestation to 14 years; samples from unaffected people served as a control group.
Three different quantification methods showed that SMN protein levels in the brain, spinal cord, and muscles are normally high during the second trimester of fetal development (weeks 14–26), and decline between the third trimester (weeks 27–40) and a baby’s first three months. These three months before and after birth are called the perinatal period.
This SMN time-sensitive dynamic was found in tissues from people with and without SMA, but SMN levels in patients were five to six times lower than in controls (six times lower at ages 0–3 months; five times in a prenatal sample). After the first three months of life, no significant differences in SMN levels were found between the two groups.
“Elevated SMN levels early in development suggest a particular need for SMN in the CNS [central nervous system; spinal cord and brain] during gestational and neonatal stages of motor neuron development,” the researchers wrote.
These results support the start of SMN-inducing therapies as soon as possible, they said, and also raise the possibility that “SMN induction prior to birth will be required for optimal patient outcomes at least in some patients.”
While SMN2 mRNA levels decreased in the last gestational trimester, a significant decrease of SMN1 mRNA levels was only seen in samples from children.
Given that SMA patients lack the SMN protein produced by SMN1, “this earlier decrease of SMN2 [mRNA] could further contribute to earlier developmental reductions in SMN protein in SMA patients compared with controls,” the researchers wrote.
Among tissues isolated from SMA patients treated with Spinraza (injected directly into the spinal canal), higher ASO concentrations were linked to higher SMN2 mRNA levels. However, this was restricted to the lumbar/sacral and thoracic regions of the spinal cord (lower and mid-back areas), where increased levels of Spinraza were found. Modest levels of ASO were also found in the brain.
“Limited [Spinraza] distribution to [anterior] spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients,” the team wrote.
The research team called its results highly important for optimizing SMA treatment, and recommended future studies into improving the delivery and distribution of ASO treatments like Spinraza.
“Whether larger volumes or higher amounts of nusinersen would improve ASO distribution in older patients is an important area for future investigation,” the study noted.
Of note, a global Phase 2/3 clinical trial (NCT04089566), called DEVOTE, looking into the safety and effectiveness of higher Spinraza doses in up to 125 people with infantile- or later-onset SMA is set to open early next year.
Wider use of newborn screening programs for SMA is crucial, the study stressed.
“As of March 2019, 18 states have begun to develop and implement [SMA] screening programs,” it concluded. “The data presented here emphasize the urgency of this effort as well as the importance of mobilizing infrastructure to provide SMN induction treatment as soon after birth as possible.”