Summer is closing with an abundance of new data on SMA. Studies aimed at understanding the disease process continue to provide information on its underlying mechanisms. At the same time, careful investigations of therapeutics are highlighting the potential of these interventions and identifying critical questions for future research, as well as those requiring ethical and policy considerations. 

Below is a roundup of the latest in SMA research. 

Understanding SMA

Mechanisms of exercise-induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy-like mice.1

This paper describes results of a study investigating the cellular and molecular mechanisms that mediate the benefits of exercise in those with SMA. According to the researchers’ data, even a single bout of physical activity is associated with molecular changes that lead to modifications in SMN expression in muscle. 

Read more here. 

Hyperexcitability precedes motoneuron loss in the Smn2B/-mouse model of spinal muscular atrophy.2

To investigate physiological functioning in motor neurons in those with SMA, the authors of this study looked at motor neuron excitability in an animal model of the disease. They found that the motor neurons had reduced action potential thresholds indicative of altered voltage-gated sodium channel activity. These results provide insight into the physiological dysfunction that precedes death of motor neurons in SMA – namely, their hyperexcitability.

Read more here.

Green kiwifruit extracts protect motor neurons from death in a spinal muscular atrophy model in Caenorhabditis elegans.3

Based on previous findings that kiwifruit can be neuroprotective, researchers who authored this study aimed to determine how the fruit may help those with SMA. Using a C. elegans model, the scientists found that green kiwifruit – but not yellow kiwifruit – may exert protection over motor neurons in SMA.

Read more here.

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.4

This paper describes an investigation into how lipid metabolism may be altered in people with SMA. Through a combination of clinical data and transcript profiling from mouse models of the disease, the researchers identified specific fatty acid metabolism abnormalities associated with SMA. The results suggest that there may be value to specific nutritional support in those with SMA.

Read more here.

Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy.5

To study the molecular mechanisms underlying cardiac pathology that is often observed in SMA, researchers employed quantitative proteomics analysis. In mouse models of SMA, the researchers identified increased cardiac lamin A/C levels. According to the researchers, these findings point to a potential therapeutic target for cardiac defects in those with SMA.

Read more here.

Recent Review:

  • Alternative splicing of ALS genes: Misregulation and potential therapies.6

In this review, the impact and mechanisms of alternative splicing that affect RNA processing in SMA and other neurodegenerative diseases is discussed. The authors also address gene therapy approaches and RNA technologies that may be useful in affecting splicing and helping patients.

Read more here.

  • Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy.7

This review provides a comprehensive view of infantile-onset SMA. The authors discuss the latest in our understanding of the biology of the disease, the search for effective therapies, the details of current treatment options, and the direction of the relevant medical fields.

Read more here.

Treating SMA

AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of Spinal Muscular Atrophy.8

The authors of this study investigated the effects of the viral delivery of a tubulin depolymerizing protein, Stathmin-1 (STMN1), on a mouse model of SMA. The results showed that this protein improved several hallmarks of the disease, including motor neuron preservation, motor function, and neuromuscular junction pathology. These effects were achieved independent of enhancing SMN protein function, which points to the value of SMN-independent therapies for the treatment of SMA.  

Read more here.

AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative study with a prospective natural history cohort.9

This article describes a study of the effects of onasemnogene abeparvovec in SMA1 infants compared to a natural history cohort and healthy infants. The results showed that onasemnogene abeparvovec benefitted the infants with SMA in several ways, including enhancing survival and improving motor function. The infants who received onasemnogene abeparvovec achieved specific motor milestones like walking or sitting without assistance.

Read more here.

An integrated safety analysis of infants and children with symptomatic spinal muscular atrophy (SMA) treated with nusinersen in seven clinical trials.10

In this paper, the authors describe the results of a study into the safety of nusinersen in infants and children with SMA. According to the authors, most adverse events that occurred in those treated with nusinersen were consistent with what would typically be expected in those with SMA or those undergoing lumbar puncture procedures. The authors therefore conclude that nusinersen has a favorable safety profile in children with both symptomatic infantile SMA and later-onset SMA. 

Read more here.

Recent Reviews:

  • Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review.11

This new review covers in detail the application of the antisense oligonucleotide drug, nusinersen, in SMA. It also discusses gaps in our understanding of the impact of the drug.

Read more here. 

  • Therapeutic advances in SMA.12

In this review, advances in therapies for 5q-associated SMA are discussed. While the authors make a case for the value of newborn screening, they also present challenges related to drug administration and the need for long-term studies to provide a more comprehensive understanding of the impacts of specific treatments.

Read more here. 

From clinical trials to clinical practice: Practical considerations for gene replacement therapy in SMA Type 1.13

Following the FDA approval of the gene replacement therapy onasemnogene abeparvovec (Zolgensma, previously also referred to as AVXS-101) for the treatment of SMA in May, this review was developed to provide a comprehensive picture of this approach to the disease. The authors describe the rationale for using gene replacement therapy in those with SMA as well as the details of the relevant clinical trials and how Zolgensma can best be applied in clinical practice.

Read more here.

Recent Chapter:

  • Evaluation of cell-penetrating peptide delivery of antisense oligonucleotides for therapeutic dfficacy in spinal muscular atrophy.14

This chapter in Methods in Molecular Biology describes techniques for using cell-penetrating peptides (CPPs) to systemically deliver antisense oligonucleotides to treat SMA. 

Read more here. 

Managing SMA

Exercise combined with electrotherapy enhances motor function in an adolescent with spinal muscular atrophy type III.15

Though electrotherapy has been shown to improve motor function, enhance muscle mass, and enable physical activity, there has been little investigation into its impact on those with SMA. This case report describes a 13-year old SMA type 3 patient who participated in an 18-week strengthening program that included neuromuscular electrical stimulation and functional electrical stimulation and experienced improvements in motor functioning. According to the researchers, there needs to be more awareness about the potential of electrotherapy to help SMA patients as well as more research into how this intervention can best be applied to this population.

Read more here. 

Decision-making regarding ventilator support in children with SMA type 1-A cross-sectional survey among physicians.16

Whether to provide infants with SMA type 1 with ventilator support has been a topic of debate in the medical community. This article describes a study into how physicians make decisions regarding ventilator support in children with SMA type 1. The results showed a wide range of perspectives on the issue. Critically, the researchers found that regardless of the physician’s attitude, this attitude tended to influence informed consent outcomes and choices for emergency scenario management.

Read more here. 

Recent Review:

Gene therapy.17

This review provides a comprehensive overview of the principles and science of gene therapy, as well as details of the gene therapies that have been approved, safety, and future considerations. Spinraza, also known as nusinersen was one of the initial 6 gene therapies approved by the FDA. It use in SMA is also discussed. 

Read more here. 

Patient Focus and Policy Implications

High-throughput genetic newborn screening for spinal muscular atrophy by rapid nucleic acid extraction from dried blood spots and 384-well qPCR.18

This paper describes the development and testing of a nucleic acid-based assay for genetic newborn screening for SMA. The technique, which involves quantitative PCT to identify a homozygous deletion of exon 7 of the SMN1 gene, has to date provided no false-positive, false-negative, or invalid results. According to the researchers, this approach could help with the early identification and treatment of SMA, even before symptom onset.

Read more here.

Spinal muscular atrophy: Past, present, and future.19

This review covers fundamentals related to SMA and discusses the benefits and controversies surrounding newborn screening. While the authors support newborn screening for SMA, they also point to the need for a long-term follow-up registry that allows for the tracking of those who are screened so that the risks and benefits of screening can be better understood over time. 

Read more here. 

Onasemnogene abeparvovec for spinal muscular atrophy: The costlier drug ever.20

In this article, the author points to the $2.125 million price tag on Zolgensma but point out that the FDA approval should allow for a future cost reduction. The FDA provided Zolgensma with orphan drug designations as well as with fast track, breakthrough therapy, priority review and also offered the manufacturer a rare pediatric disease priority review voucher aimed at incentivizing the development of this type of drug. 

Read more here. 

References

1. Ng SY, Mikhail A, Ljubicic V. Mechanisms of exercise-induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy-like mice. J Physiol. July 2019. doi:10.1113/JP278454

2. Quinlan KA, Reedich E, Arnold WD, et al. Hyperexcitability precedes motoneuron loss in the Smn(2B/-)mouse model of spinal  muscular atrophy. J Neurophysiol. July 2019. doi:10.1152/jn.00652.2018

3. Mazzarella N, Giangrieco I, Visone S, et al. Green kiwifruit extracts protect motor neurons from death in a spinal muscular atrophy model in Caenorhabditis elegans. Food Sci Nutr. 2019;7(7):2327-2335. doi:10.1002/fsn3.1078

4. Deguise M-O, Baranello G, Mastella C, et al. Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Ann Clin Transl Neurol. 2019;6(8):1519-1532. doi:10.1002/acn3.50855

5. Soltic D, Shorrock HK, Allardyce H, et al. Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. August 2019. doi:10.1093/hmg/ddz195

6. Perrone B, La Cognata V, Sprovieri T, et al. Alternative Splicing of ALS Genes: Misregulation and Potential Therapies. Cell Mol Neurobiol. August 2019. doi:10.1007/s10571-019-00717-0

7. Jha NN, Kim J-K, Monani UR. Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy. Future Neurol. 2018;13(3):161-172. doi:10.2217/fnl-2018-0008

8. Villalon E, Kline RA, Smith CE, et al. AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse  model of Spinal Muscular Atrophy. Hum Mol Genet. July 2019. doi:10.1093/hmg/ddz188

9. Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort. J Neuromuscul Dis. July 2019. doi:10.3233/JND-190403

10. Darras BT, Farrar MA, Mercuri E, et al. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. August 2019. doi:10.1007/s40263-019-00656-w

11. Meylemans A, De Bleecker J. Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review. Acta Neurol Belg. August 2019. doi:10.1007/s13760-019-01199-z

12. Ludolph AC, Wurster CD. Therapeutic advances in SMA. Curr Opin Neurol. August 2019. doi:10.1097/WCO.0000000000000738

13. Al-Zaidy SA, Mendell JR. From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1. Pediatr Neurol. June 2019. doi:10.1016/j.pediatrneurol.2019.06.007

14. Hammond SM, Abendroth F, Gait MJ, Wood MJA. Evaluation of Cell-Penetrating Peptide Delivery of Antisense Oligonucleotides for Therapeutic Efficacy in Spinal Muscular Atrophy. Methods Mol Biol. 2019;2036:221-236. doi:10.1007/978-1-4939-9670-4_13

15. Gobbo M, Lazzarini S, Vacchi L, et al. Exercise Combined with Electrotherapy Enhances Motor Function in an Adolescent with Spinal Muscular Atrophy Type III. Case Rep Neurol Med. 2019;2019:4839793. doi:10.1155/2019/4839793

16. Pechmann A, Langer T, Kirschner J. Decision-Making Regarding Ventilator Support in Children with SMA Type 1-A Cross-Sectional Survey among Physicians. Neuropediatrics. August 2019. doi:10.1055/s-0039-1694986

17. High KA, Roncarolo MG. Gene Therapy. N Engl J Med. 2019;381(5):455-464. doi:10.1056/NEJMra1706910

18. Czibere L, Burggraf S, Fleige T, et al. High-throughput genetic newborn screening for spinal muscular atrophy by rapid nucleic acid extraction from dried blood spots and 384-well qPCR. Eur J Hum Genet. July 2019. doi:10.1038/s41431-019-0476-4

19. Ross LF, Kwon JM. Spinal Muscular Atrophy: Past, Present, and Future. Neoreviews. 2019;20(8):e437-e451. doi:10.1542/neo.20-8-e437

20. Mahajan R. Onasemnogene Abeparvovec for Spinal Muscular Atrophy: The Costlier Drug Ever. Int J Appl basic Med Res. 2019;9(3):127-128. doi:10.4103/ijabmr.IJABMR_190_19