There have been several recent publications related to spinal muscular atrophy (SMA). Below is a summary of some pieces that add to our understanding of the disease.
Identifying Modifiers of SMN Proteins
A study out of Bethesda, Maryland, published in Cell Reports, aimed at investigating the mechanisms by which survival motor neuron (SMN) proteins are regulated.1 Because current treatments for SMA that improve survival do not always also confer benefits in terms of motor functions, it is becoming increasingly clear that combination treatments may improve outcomes to a greater extent than individual therapies alone.
Through a genome-wide RNAi screen, the authors showed that SMN levels are increased when nuclear and cytoplasmic RNA transport is regulated via the reduced expression of transcription export complex components. These findings may have implications for new avenues of treatment for SMA.
Stabilizing Synapses in Patients With SMA
Because synapses often degenerate early in the course of SMA, there has been significant focus on identifying potential means of stabilizing synapses in those with the disease. Nonetheless, compounds that effectively provide this type of stabilization have been elusive.
This article describes a preclinical study that employed an automated screening paradigm to identify relevant synapse-stabilizing compounds.2 Based on the observation that axon length can help predict synapse stability, nearly 1000 small molecules were screened for their ability to rescue the length of motor axons. Dipyridamole, an adenosine uptake inhibitor, was the most effective compound.
In addition to identifying a small molecule that should be further explored for its ability to stabilize synapses in SMA, the research also provided information on a platform that could be useful for screening compounds for other uses in SMA. This type of automated process could significantly increase the efficiency of finding promising molecules for SMA interventions.
A Potential New Pathway for SMA Therapies
In a new article published in the Proceedings of the National Academy of Sciences, researchers describe their findings related to motoneuron rescue3. Given that SMA patients already receive therapies that enhance SMN, complementary approaches are likely to be most effective if they work through an SMN-independent mechanism.
Here, the researchers used an animal model of SMA to investigate what abnormal signaling may occur in the disease before symptoms arise. The research revealed that downregulated proteins that can be observed presymptomatically could be targeted to rescue motor functions, even after motoneuron degeneration has begun. Critically, this rescue mechanism relied on the MEK/ERK pathway, suggesting that this pathway may offer new therapeutic opportunities in SMA.
A Case Study of SMA With Congenital Bone Fractures
A case of spinal muscular atrophy with congenital bone fractures 2 (SMABF2) was described in this report4. The infant who displayed several features of SMABF2 also showed certain unique characteristics. These included a cleft palate, transverse liver, small spleen, impaired coagulation, and blood clots blocking the lungs that had a chondroid appearance.
Trio whole genome sequencing revealed that the infant inherited ASCC1 variants both maternally and paternally. The novel intronic variant in this case of SMABF2 partially disrupted RNA splicing. These findings add clinical and mechanistic information on the ways in which SMA can occur and manifest.
1. McCormack NM, Abera MB, Arnold ES, et al. A high-throughput genome-wide RNAi screen identifies modifiers of survival motor neuron protein. Cell Rep. 2021;35(6):109125. doi:10.1016/j.celrep.2021.109125
2. Oprişoreanu A-M, Smith HL, Krix S, et al. Automated in vivo drug screen in zebrafish identifies synapse-stabilising drugs with relevance to spinal muscular atrophy. Dis Model Mech. 2021;14(4). doi:10.1242/dmm.047761
3. Hensel N, Cieri F, Santonicola P, et al. Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2021;118(18):e2007785118. doi:10.1073/pnas.20077851184. Rosano KK, Wegner DJ, Shinawi M, et al. Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2). Am J Med Genet A. Published online May 1, 2021. doi:10.1002/ajmg.a.62219