“The race is not to the swift, but time and chance happens to them all” is an ancient saying that illustrates how even the best laid plans are subject to the dictates of chance and opportunity.
In medicine, particularly in the field of rare diseases, the early detection of a disease and the early initiation of treatment usually translates to better outcomes. Some diseases can be picked up from birth; others are insidious and only become obvious once they have progressed significantly.
Spinal muscular atrophy (SMA) is a genetic disease that causes the degeneration of lower motor neurons and muscular atrophy, manifesting primarily as muscle weakness and immobility. Patients with type 1 of the disease experience symptoms within months of birth and are unable to sit unsupported. These patients usually have failure to thrive and suffer from an extremely poor prognosis.
Patients with type 2 of the disease typically experience symptom onset between 7 and 18 months. They are usually able to sit without support but cannot walk independently. In addition, they may suffer from swallowing and chewing difficulties, compromising their nutritional status. They may also need mechanical ventilation due to respiratory difficulties.
Read more about SMA etiology
The window between diagnosis and symptom onset is short across all subtypes of SMA. Studies indicate that the lag between symptom onset to diagnosis for SMA type 1 is 3.6 months. In SMA type 2, the lag is 14.3 months, and 43.6 months for SMA type 3.
Therapeutic advancements in the field of SMA over the last decade have been astonishing, and we now have 3 forms of therapies available to treat patients with SMA. The first is nusinersen, an antisense oligonucleotide targeting SMN2. The second is onasemongene abeparvovec, a gene replacement therapy. The third is risdiplam, the most recently approved therapy for SMA; it too works by targeting SMN2.
As mentioned, patients with SMA tend to present with developmental difficulties. Scientists have suggested that this is because the SMN protein is crucial for the development of the nervous system. As such, the timing of treatment initiation is crucial in order to secure better long-term outcomes.
“A wealth of preclinical data has shown that the therapeutic time-window to treat SMA is narrow,” Motyl and Gillingwater wrote in Cell Reports Medicine.
Studies indicate that developmental defects can be detected prenatally, meaning that the phenotype of this disease can manifest itself before birth. Scientists have observed prenatal systemic changes and underlying motor neuron degeneration.
Mice studies have illustrated the importance of starting treatment early. Scientists reported that early treatment in SMA mice improves motor function and extends survival. Studies involving human patients have also indicated that early therapy initiation leads to better results: a study involving nusinersen therapy in presymptomatic infants with 2 or 3 copies of SMN2 significantly improves outcomes compared to the initiation of treatment in symptomatic children.
The Benefits of Early Treatment
Further evidence for the initiation of treatment in presymptomatic children were provided by the results of a phase 3 clinical trial for onasemnogene abeparvovec conducted by Strauss et al.
“Onasemnogene abeparvovec is an in vivo adeno-associated virus serotype 9 (AAV9) gene replacement therapy that delivers the SMN transgene under a ubiquitous promoter into target cells, through a one-time [intravenous] infusion,” Kichula and colleagues wrote in Muscle & Nerve.
AAV gene therapy has garnered intense interest because it offers a number of advantages over other viral vectors. AAV gene therapy is not known to cause any human diseases, and the activation of the innate immunity is lower compared with adenovirus vectors. In addition, they have a lower risk of genomic integration due to the fact that the transgene is maintained as an episome.
In the phase 3 clinical trial for onasemnogene abeparvovec, treatment was initiated in presymptomatic infants at risk of developing either SMA type 1 or type 2. The research team initiated treatment after genetic confirmation in 14 infants with 2 copies of SMN2 and 15 infants with 3 copies of SMN2. The infants received therapeutic intervention within 6 weeks of life, prior to symptom onset.
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The results of the presymptomatic treatment of infants with SMA allowed them to achieve developmental milestones greater and earlier compared to untreated patients or patients who only received treatment once they became symptomatic.
“While the cohorts were small, the findings are unequivocal: treatment needs to be started as early as possible to maximize therapeutic benefits,” Motyl and Gillingwater wrote.
However, the presymptomatic treatment of infants with SMA is only possible with newborn screening. As mentioned, patients with all subtypes of SMA become symptomatic within months/years of birth. Therefore, any screening program that takes place after birth is likely to be too late.
Fortunately, newborn screening for SMA is available in many parts of the world, including in countries such as Australia, Germany, Japan, and Taiwan. In the United States, SMA newborn screening is available in 46 states.
While the implementation of newborn screening inevitably involves some costs, it ultimately saves individual families from having to spend more as a consequence of having a child with severe SMA. An Australian study assessing the costs of newborn screening coupled with early gene therapy reported that they generally fall within acceptable thresholds for most families.
“The publications by Strauss et al provide the first direct clinical evidence that presymptomatic treatment with gene therapy enhances its therapeutic efficacy in infants with SMA,” Motyl and Gillingwater wrote. “This should encourage the SMA community and stakeholders to consider presymptomatic timing as optimal for therapy delivery and provide support to convince policy makers of the importance and value of [newborn screening] for SMA.”
Motyl AAL, Gillingwater TH. Timing is everything: clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy. Cell Rep Med. Published online August 16, 2022. doi:10.1016/j.xcrm.2022.100725
Kichula EA, Proud CM, Farrar MA, et al. Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy. Muscle Nerve. Published online July 20, 2021. doi:10.1002/mus.27363
Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the phase III SPR1NT trial. Nat Med. Published online June 17, 2022. doi:10.1038/s41591-022-01866-4