Much of the most recent research regarding spinal muscular atrophy (SMA) has focused on understanding the mechanisms mediating the disease as well as the clinical value of different pharmaceutical interventions. There have been several reviews on the latter topic, with a continuing emphasis on nusinersen, the first drug approved to treat SMA. Additionally, there are new data related to the management of SMA, patient perspectives on the disease, and policy issues surrounding the diagnosis and treatment of the disease. 

Below is a roundup of the most recent literature on SMA.

Understanding SMA

NFL is a marker of treatment response in children with SMA treated with nusinersen.1

Neurofilament light protein (NFL) may be a promising biomarker for monitoring SMA patients’ response to nusinersen. A new study found that the drug reduced levels of NFL in children with SMA type 1 and 2 copies of the SMN2 gene and that the magnitude of the reduction correlated with improvements in motor symptoms. 

Read more here. 

Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis.2

Researchers have conducted whole-exome sequencing (WES) on a 2 year-old boy with congenital spinal muscular atrophy and arthrogyrposis (CSMAA) and his family members to identify the genetic cause of the recessive form of this disease. Their results indicate that the culprit is a novel homozygous mutation in the transient receptor potential vanilloid 4 (TRPV4). 

Read more here. 

Defective Expression of Mitochondrial, Vacuolar H+-ATPase and Histone Genes in a C. elegans Model of SMA.3

A new study conducted on C. elegans to evaluate how the survival motor neuron gene 1 (SMN-1) influences RNA splicing and the expression of other genes has shown that SMN-1 can affect the expression of mitochondrial and histone genes through its interaction with the UAF-1 gene, which encodes the splicing factor, U2AF large subunit.

Read more here. 

Nerve sprouting capacity in a pharmacologically induced mouse model of spinal muscular atrophy.4

New data show that the splicing modifier, SMN-C1 can lead to the terminal sprouting that is involved in muscle fiber reinnervation. Researchers observed this effect to be dose-dependent in pharmacological SMA mice. 

Read more here. 

Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA.5

This preclinical mouse study demonstrates the potential of U1 small nuclear ribonucleoproteins (U1 snRNP) delivered through adeno-associated virus AAV9 as  therapeutic targets for SMA. 

Read more here. 

Recent Review:

  • Dissecting Motor Neuron Disease With Drosophila melanogaster6 

In this review, researchers from the University of Sydney cover how Drosophila fly models are currently used to investigate the genetic components of motor neuron disease, including SMA. 

Read the review here. 

Treating SMA

Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy.7

New preclinical research has shown that alpha-COP, a subunit of non-clathrin-coated vesicular coat proteins (COPs), modifies the SMA disease phenotype in mice. These data suggest that alpha-COP may be a promising therapeutic target for SMA.

Read more here.

The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular Atrophy Model.8

The results from an investigation into the effects of levetiracetam, an anti-epileptic drug, on spinal motor neurons from stem cells of SMA patients, suggest that the drug may be neuroprotective. Specifically, levetiracetam was able to enhance neurite elongation, reduce the expression of cleaved-caspase 3, and improve mitochondrial function. However, levetiracetam did not modify SMN protein expression in these cells. 

Read more here. 

Recent Reviews:

  • Antisense oligonucleotides: A primer9

This review covers the latest information on the potential of antisense oligonucleotides to treat SMA and other neurodegenerative diseases. 

Read the review here. 

  • Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy10

In this review, the authors focus specifically on the antisense oligonucleotide, nusinersen, and its application in SMA. This paper provides a comprehensive picture of the role of nusinersen in SMA treatment.

Read the review here. 

  • Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis11

The results of this systematic review suggest that valproic acid is effective in improving gross motor functions for those with SMA but not in treating other types of motor function or in treating respiratory function.

Read the review here. 

  • Physical exercise training for type 3 spinal muscular atrophy12

Through a literature review, the authors of this article make the argument that it is still unclear whether strengthening and aerobic exercise helps or hurts SMA type 3 patients and suggest the need for more research to support the development of exercise guidelines for this set of patients.

Read the review here. 

  • Treating Disease at the RNA Level with Oligonucleotides13

This review covers different oligonucleotide drugs and their applications and discusses the direction of clinical development in this space.

Read the review here. 

  • Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases14

Data on the use of adeno-associated virus in the treatment of neurodegenerative diseases such as SMA are discussed in this review.

Read the review here. 

  • Long-term benefits of nusinersen in later-onset spinal muscular atrophy15

Much of the information to date on nusinersen has focused on the short-term effects of the drug. Now that the drug has been employed over extended periods of time, data are accumulating to demonstrate its long-term impacts. This review discusses how nusinersen can help those with later-onset SMA over the long-term.

Read the review here. 

  • Spinal Muscular Atrophy and Common Therapeutic Advances16

In this review, the authors cover the therapeutic options for SMA patients with an emphasis on newer approaches like gene therapy. 

Read the review here. 

Managing SMA

Effects of long-term non-invasive ventilation on sleep structure in children with Spinal Muscular Atrophy type 2.17 

The effect of long-term non-invasive positive pressure ventilation (LTNPPV) on the sleep microstructure of children with SMA type 2 was recently investigated for the first time. The results, reported in this article, show that LTNPPV leads to small sleep changes and suggest that this approach may to some extent improve arousability in this group of children with SMA.

Read more here. 

Thoracic circumference: A new outcome measure in spinal muscular atrophy type 1?18

This study showed that the ratio of thoracic circumference to head circumference decreased over time in SMA type 1 patients as the disease progressed. The results suggest that this ratio may provide meaningful information on the severity of disease as well as prognosis in patients with SMA type 1. 

Read more here. 

Patient Focus and Policy Implications

Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.19

A new publication in the Journal of Market Access & Health Policy states that single-dose onasemnogene abeparvocec (AVXS-101) is cost-effective compared to chronic nusinersen in U.S. patients with SMA1 when considered from the perspective of the commercial payer. 

Read more here.

Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community.20

This paper describes findings from the first-ever Benefit-Risk Survey related to SMA, which was launched by Cure SMA to inform regulators about patient perceptions related to potential SMA therapies. Approximately 75% of the 298 survey responses came from caregivers, with the remaining responses coming from adults with SMA. Of note, respondents said that risks that were life-threatening or that could diminish quality of life were the least tolerable, whereas those associated with invasive treatment or common, non-threatening side effects were the most tolerable risks. 

Read more here.

Implementing a Global Expanded Access Program (EAP) for Infantile-Onset Spinal Muscular Atrophy (Type I): Understanding the Imperative, Impact and Challenges.21

A new publication in the Journal of Neuromuscular Diseases discusses findings and considerations related to an expanded access program (EAP) that has been providing nusinersen therapy to individuals with the most severe form of SMA who do not have alternative treatment options. 

Read more here. 

Recent Reviews:

  • Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps22

This review covers information on newborn screening in neuromuscular disorders like SMA and considerations related to the expansion of these screenings to identify more infants that could benefit from early interventions.

Read the review here. 

As innovation spurs advances in therapeutics for SMA, considerations for genetic counseling must be updated to account for the new therapeutic landscape and the implications for patients. This review discusses the latest details relevant for SMA genetic counseling.

Read the review here. 

  • Quality of life of patients with spinal muscular atrophy: A systematic review24

This review covers what is known about quality of life in patients with SMA. According to the paper, quality of life is reduced in SMA patients mainly because of the impact of the disease on physical health but more research is needed to understand the intricacies of how different aspects of the disease impact quality of life. 

Read the review here. 

References

1. Olsson B, Alberg L, Cullen NC, et al. NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol. May 2019. doi:10.1007/s00415-019-09389-8

2. Velilla J, Marchetti MM, Toth-Petroczy A, et al. Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis. Neurol Genet. 2019;5(2):e312. doi:10.1212/NXG.0000000000000312

3. Gao X, Xu J, Chen H, et al. Defective Expression of Mitochondrial, Vacuolar H(+)-ATPase and Histone Genes in  a C. elegans Model of SMA. Front Genet. 2019;10:410. doi:10.3389/fgene.2019.00410

4. Rimer M, Seaberg BL, Yen P-F, et al. Nerve sprouting capacity in a pharmacologically induced mouse model of spinal muscular atrophy. Sci Rep. 2019;9(1):7799. doi:10.1038/s41598-019-44222-2

5. Donadon I, Bussani E, Riccardi F, et al. Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA. Nucleic Acids Res. May 2019. doi:10.1093/nar/gkz469

6. Walters R, Manion J, Neely GG. Dissecting Motor Neuron Disease With Drosophila melanogaster. Front Neurosci. 2019;13:331. doi:10.3389/fnins.2019.00331

7. Custer SK, Astroski JW, Li HX, Androphy EJ. Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy. Biochem Biophys Res Commun. 2019;514(2):530-537. doi:10.1016/j.bbrc.2019.04.176

8. Ando S, Funato M, Ohuchi K, et al. The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular  Atrophy Model. Neurochem Res. May 2019. doi:10.1007/s11064-019-02814-4

9. Scoles DR, Minikel E V, Pulst SM. Antisense oligonucleotides: A primer. Neurol Genet. 2019;5(2):e323. doi:10.1212/NXG.0000000000000323

10. Neil EE, Bisaccia EK. Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy. J Pediatr Pharmacol Ther. 2019;24(3):194-203. doi:10.5863/1551-6776-24.3.194

11. Elshafay A, Hieu TH, Doheim MF, et al. Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis. CNS Drugs. 2019;33(3):239-250. doi:10.1007/s40263-019-00606-6

12. Bartels B, Montes J, van der Pol WL, de Groot JF. Physical exercise training for type 3 spinal muscular atrophy. Cochrane database Syst Rev. 2019;3:CD012120. doi:10.1002/14651858.CD012120.pub2

13. Levin AA. Treating Disease at the RNA Level with Oligonucleotides. N Engl J Med. 2019;380(1):57-70. doi:10.1056/NEJMra1705346

14. Qu Y, Liu Y, Noor AF, Tran J, Li R. Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases. Neural Regen Res. 2019;14(6):931-938. doi:10.4103/1673-5374.250570

15. Fyfe I. Long-term benefits of nusinersen in later-onset spinal muscular atrophy. Nat Rev Neurol. May 2019. doi:10.1038/s41582-019-0202-4

16. Bozorg Qomi S, Asghari A, Salmaninejad A, Mojarrad M. Spinal Muscular Atrophy and Common Therapeutic Advances. Fetal Pediatr Pathol. 2019;38(3):226-238. doi:10.1080/15513815.2018.1520374

17. Verrillo E, Pavone M, Bruni O, et al. Effects of long-term non-invasive ventilation on sleep structure in children with Spinal Muscular Atrophy type 2. Sleep Med. 2019;58:82-87. doi:10.1016/j.sleep.2019.03.005

18. Ropars J, Barnerias C, Hully M, et al. Thoracic circumference: A new outcome measure in spinal muscular atrophy type 1? Neuromuscul Disord. March 2019. doi:10.1016/j.nmd.2019.03.003

19. Malone DC, Dean R, Arjunji R, et al. Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients. J Mark access Heal policy. 2019;7(1):1601484. doi:10.1080/20016689.2019.1601484

20. Cruz R, Belter L, Wasnock M, Nazarelli A, Jarecki J. Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever  Study to Assess Risk Tolerance in the SMA Patient Community. Clin Ther. 2019;41(5):943-960.e4. doi:10.1016/j.clinthera.2019.03.012

21. Yong J, Moffett M, Lucas S. Implementing a Global Expanded Access Program (EAP) for Infantile-Onset Spinal Muscular Atrophy (Type I): Understanding the Imperative, Impact and Challenges. J Neuromuscul Dis. 2019;6(2):227-231. doi:10.3233/JND-190387

22. Baker M, Griggs R, Byrne B, et al. Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps. JAMA Neurol. May 2019. doi:10.1001/jamaneurol.2019.1206

23. Serra-Juhe C, Tizzano EF. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur J Hum Genet. May 2019. doi:10.1038/s41431-019-0415-4

24. Landfeldt E, Edstrom J, Sejersen T, Tulinius M, Lochmuller H, Kirschner J. Quality of life of patients with spinal muscular atrophy: A systematic review. Eur J Paediatr Neurol. March 2019. doi:10.1016/j.ejpn.2019.03.004