This month has seen a surge of publications focused on SMA treatments, with a trend towards optimizing various aspects of nusinersen treatment. Research has also continued in areas related to molecular mechanisms of the disease, clinical manifestations, and management protocols. 

Here’s a roundup of the latest in SMA research and related commentary.

Understanding SMA

Acid ceramidase depletion impairs neuronal survival and induces morphological defects in neurites associated with altered gene transcription and sphingolipid content.1 

Based on the observation that mutations to the gene ASAH1 lead to progressive myoclonic epilepsy (SMA-PME), researchers have characterized a stable ASAH1 knockdown cell line and reported on it in this paper. The resulting cells have displayed a reduction in proliferation, which occurred due to enhanced apoptosis. Further analysis revealed that acid ceramidase, which is encoded by ASAH1, plays a critical neuronal role and that when acid ceramidase is depleted, neuropathology consistent with SMA-PME develops.

Read more here. 

Recent Reviews:

  • Walking and weakness in children: a narrative review of gait and functional ambulation in paediatric neuromuscular disease.3

This review examines aspects of gait, including gait speed, gait-related balance, qualitative aspects of gait function, endurance, ambulatory capacity, and timed function in children with neuromuscular disease. The researchers found that those with SMA type 3 were more limited in their endurance and ambulatory capacity than their developmentally normal counterparts. According to the authors, more information is needed about gait function in neuromuscular disease to improve both research and clinical interventions.

Read more here.

  • New perspectives for selective NCX activators in neurodegenerative diseases.2

This review describes compounds that activate and inhibit sodium calcium exchanger (NCX) isoforms, which are implicated in neurological disorders like SMA. The authors also provide an analysis of ways to strategically intervene in SMA by changes NCX isoforms.

Read more here.

Treating SMA

Radiation dose reduction for CT-guided intrathecal nusinersen administration in adult patients with spinal muscular atrophy.4

Nusinersen treatment in SMA patients with scoliosis and spondylodesis requires image guidance, which is normally conducted with multi-detector computer tomography (MDCT). Because treatment is often needed over a long-term, it is important to determine ways to minimize radiation exposure, particuclarly in young SMA patients. This paper describes a study that demonstrates the value of a low-dose MDCT protocol that the authors claim may be a viable option for intrathecal nusinersen administration in young adults. 

Read more here.

Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model.5

This paper compares two modifications of systemic antisense oligonucleotides in a mouse model of severe SMA. Like nusinersen, both modifications are shown to be effective splice-switching antisense oligonucleotides, though each has relative advantages. Specifically, one of the modifications was more effective at lower doses and had more persistent effects, whereas the other modification more readily crossed immature blood brain barriers and produced more robust initial effects.

Read more here.

The need for SMN-independent treatments of spinal muscular atrophy (SMA) to complement SMN-enhancing drugs.6

This paper provides information on newly approved drugs for SMA that act by enhancing SMN levels. Despite the significant benefits observed with these drugs, some patients are non-responders or are past the point at which SMN restoration is helpful. The authors argue that there is therefore a need to develop complementary strategies that are SMN-independent, and they discuss the way such drugs could be used in a clinical setting.

Read more here.

SMA: from gene discovery to gene therapy.10

In this paper, the authors describe a startup company that has applied the approach of using a single intravenous injection of an adeno-associated virus expressing SMN1, which has been previously tested preclinically, in children diagnosed with SMA type 1. After applying this Zolgensma drug through an arm or leg vein, the startup researchers observed increases in these children’s life span. 

Read more here.

  • Management of neuroinflammatory responses to AAV-mediated gene therapies for neurodegenerative diseases.7

In this review, the authors discuss the potential for delivering adeno-associated virus mediated gene therapies directly to the central nervous system. This strategy has certain advantages over systemic administration, including higher transgene expression and lower immune responses. The authors argue, however, that because direct administration to the central nervous system is also associated with problematic neuroinflammation, biomarkers that can track such neuroinflammation will be important if this administration route is to be pursued – both to understand the influence of immune reactions and to help maintain drug efficacy and safety.

Read more here.

  • Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1).8

This review summarizes what is known thus far about SMA with respiratory distress type 1 (SMARD1). The authors discuss clinical presentation, pathogenesis, and clinical management. They provide a comprehensive review of the relevant therapies, including emerging data for the potential of gene therapy in patients with SMARD1.

Read more here.

  • The light at the end of the tunnel gets vivid for spinal muscular atrophy: An Editorial Highlight for “Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy” on https://doi.org/10.1111/jnc.14953.9

This editorial discusses the potential value of a recent paper aiming to identify SMA biomarkers using high-throughput cerebrospinal fluid data. According to the authors of the editorial, because the study produced mixed data from a relatively small sample, the authors of the study did not make a strong conclusion. The editorial authors argue, however, that the data are still important to consider. Additionally, the authors emphasize that the technique involving analysis of proteomics data could be a useful way to identify drug responders and to better understand drug efficacy, disease course, and prognosis.

Read more here.

Managing SMA

Clinical practice guidelines for spinal muscular atrophy.11

This guideline presents information on SMA, including data on clinical manifestations of the disease, diagnosis and genetic counseling. The authors point to the importance of standardizing SMA diagnosis and treatment and to reduce the number of children born with the disease. 

Read more here. 

Patient Focus and Policy Implications

Spinal muscular atrophy in the black South African population: A matter of rearrangement?12

This paper highlights the observation that while approximately 94% of SMA patients worldwide have a homozygous deletion of SMN1, only about 51% of black South Africans with SMA have this type of deletion. Based on this observation, the researchers investigated the genetic cause of SMA in the black South African population. They did not, however, identify any clear pathogenic copy number variations. The authors suggest that the lack of understanding regarding the cause of SMA and the architecture of the SMN region in black South African SMA patients are important considerations for diagnosis and counseling. 

Read more here.

References

1. Kyriakou K, Lederer CW, Kleanthous M, Drousiotou A, Malekkou A. Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content. Int J Mol Sci. 2020;21(5). doi:10.3390/ijms21051607

2. Annunziato L, Secondo A, Pignataro G, Scorziello A, Molinaro P. New perspectives for selective NCX activators in neurodegenerative diseases. Cell Calcium. 2020;87:102170. doi:10.1016/j.ceca.2020.102170

3. Kennedy RA, Carroll K, McGinley JL, Paterson KL. Walking and weakness in children: a narrative review of gait and functional ambulation in paediatric neuromuscular disease. J Foot Ankle Res. 2020;13(1):10. doi:10.1186/s13047-020-0378-2

4. Cordts I, Deschauer M, Lingor P, et al. Radiation dose reduction for CT-guided intrathecal nusinersen administration in adult patients with spinal muscular atrophy. Sci Rep. 2020;10(1):3406. doi:10.1038/s41598-020-60240-x

5. Sheng L, Rigo F, Bennett CF, Krainer AR, Hua Y. Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model. Nucleic Acids Res. February 2020. doi:10.1093/nar/gkaa126

6. Hensel N, Kubinski S, Claus P. The Need for SMN-Independent Treatments of Spinal Muscular Atrophy (SMA) to Complement SMN-Enhancing Drugs. Front Neurol. 2020;11:45. doi:10.3389/fneur.2020.00045

7. Perez BA, Shutterly A, Chan YK, Byrne BJ, Corti M. Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases. Brain Sci. 2020;10(2). doi:10.3390/brainsci10020119

8. Perego MGL, Galli N, Nizzardo M, et al. Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Cell Mol Life Sci. March 2020. doi:10.1007/s00018-020-03492-0

9. Dutta D, Chandra G, Mohanakumar KP. The light at the end of the tunnel gets vivid for spinal muscular atrophy: An Editorial Highlight for “Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy” on https://doi.org/10.1111/jnc.14953. J Neurochem. March 2020. doi:10.1111/jnc.14976

10. Barkats M. [SMA: from gene discovery to gene therapy]. Med Sci (Paris). 2020;36(2):137-140. doi:10.1051/medsci/2020010

11. Association WGFPGFDATOGDMGBOCM, Pan J, Tan H, Zhou M, Liang D, Wu L. [Clinical practice guidelines for spinal muscular atrophy]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020;37(3):263-268. doi:10.3760/cma.j.issn.1003-9406.2020.03.007

12. Vorster E, Essop FB, Rodda JL, Krause A. Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement? Front Genet. 2020;11:54. doi:10.3389/fgene.2020.00054