Summer has closed with new data and news on SMA coming to the fore. Much of the research on SMA published in recent weeks has focused on how to best treat the disease, and some new debate has emerged surrounding the relative advantages of Zolgensma versus Spinraza. At the same time, investigations into the underlying causes of SMA and how to best manage the disease continue as well.

Below is a roundup of the latest in SMA research. 

Understanding SMA

ZPR1-Dependent Neurodegeneration Is Mediated by the JNK Signaling Pathway.1

This paper describes a study into the mechanism by which zinc finger protein ZPR1 deficiency in patients with SMA leads to neurodegeneration. Previous research has shown that ZPR1 interacts with the survival motor neuron (SMN) protein and is required for its accumulation. These new data reveal that the neurodegeneration that results from lower levels of ZPR1 in SMA patients is mediated by c-Jun NH2-terminal kinase (JNK) signaling. 

Read more here. 

Recent Review:

  • Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy.2

In this review, the authors discuss the need for meaningful biomarkers for SMA and describe candidate biomarkers. According to their analysis, SMN2 has the most significant influence over SMA phenotype and possesses prognostic clinical value. The authors also point to circulatory biomarkers as establishing a growing role in tracking the progression of SMA, as well as treatment response. They note that neurophysiological biomarkers are becoming useful in real-world settings for evaluating motor unit output in response to therapeutic interventions. 

Read more here.

Treating SMA

Comparisons Between Separately Conducted Clinical Trials: Letter to the Editor Regarding Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guérin A, et al. Adv Ther (2019) 36(5):1164-76. doi:10.1007/s12325-019-00923-8.3 

This letter to the editor addresses a study published earlier this year (see the original study here),4 which concluded that AVXS-101 (Zolgensma) may have certain efficacy advantages over nusinersen (Spinraza) in the treatment of infants with SMA. This letter raises concerns over the interpretation of the data. 

Read the letter here.

Response to: Alfred Sandrock, Wildon Farwell. Letter to the Editor, Comparisons Between Separately Conducted Clinical Trials: Letter to the Editor Regarding Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guérin A, et al. Adv Ther (2019) 36(5):1164-76. doi:10.1007/s12325-019-00923-8.5

This response to the above letter to the editor from the authors of the original study addresses the issues highlighted in the letter. This series of pieces represents not only an ongoing debate about the differences in value and relative benefits of Zolgensma and Spinraza in treating SMA but also demonstrates emerging thinking on what constitutes adequate data when drawing clinically meaningful insights regarding SMA treatments. 

Read the response here. 

Alternative gene therapy target identified in spinal muscular atrophy mice.6

In this article, researchers describe a new study into a potential gene therapy for SMA. The scientists delivered STMN1, the gene that encodes stathmin, a tubulin depolymerizing protein, via a viral vector to the cerebral ventricles of mice on postnatal day 2. This intervention was associated with longer survival, better performance on motor tasks, and reduced pathology in motor neurons and neuromuscular junctions compared to mice that did not receive the STMN1 gene therapy. These new data point to the possibility of a gene therapy for SMA that does not target the SMN protein.

Read more here.

CSF transplantation of a specific iPSC-derived neural stem cell subpopulation ameliorates the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1.7

This paper covers a study that addresses the practical implications of stem cell therapy for SMA patients. In this study, the ability to effectively transplant human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) in a mouse model of spinal muscular atrophy with respiratory distress type 1 (SMARD 1) is demonstrated. Not only did the cells migrate and engraft successfully, but they were detectable in the ventral horn of the spinal cord, and their presence was associated with improvements related to neuromuscular function. These results provide preclinical support for the feasibility of the use of stem cell therapies in SMA.

Read more here.

Recent Reviews:

  • The End of the Beginning: The Journey to Molecular Therapies for Spinal Muscular Atrophy.8

This editorial provides a review the history of molecular therapies for SMA. Amidst growing recognition of the potential risks and limitations of gene therapy, the authors make the important point that unlike with other rare disorders that are being treated with gene therapy, those with SMA tend to have low levels of the SMN protein, which reduces the likelihood that that the immune system will perceive the transgene product as foreign and lead to an unwanted immune response. The authors also discuss the future potential for custom-designed molecular therapies for all newborns with SMA.

Read more here. 

Managing SMA

Long-term progression in type II spinal muscular atrophy: A retrospective observational study.9

The authors of this paper describe a study on 73 patients with SMA type II that investigated how scores on the Hammersmith Functional Motor Scale-Expanded test predicted long-term disease progression. The results showed that test scores indicative of higher functional impairment at baseline were associated with earlier scoliosis onset and a greater likelihood of needing noninvasive ventilation.

Read more here. 

Bulbar Problems Self-Reported by Children and Adults with Spinal Muscular Atrophy.10

This paper describes a study on 118 SMA patients who had reported jaw problems, choking, intelligibility issues, or fatigue related to mastication. The researchers investigated the relationship between self-reported bulbar issues in SMA patients and patient age, motor function, and maximum mouth opening capacity. Their results showed that older patients with SMA type 3a were more likely to report bulbar problems than younger SMA type 3a patients and that reduced mouth opening was associated with bulbar complaints in SMA type 2 patients.

Read more here. 

Patient Focus and Policy Implications

Nusinersen for type 1 spinal muscular atrophy: A father’s perspective.11

In this Pediatrics Perspective, a physician and father of a boy with SMA who was treated with nusinersen offers his insights on the costs and benefits of this therapy for those with SMA type 1. 

Read more here.

Cigna offers new coverage program for expensive gene therapy.12

It has been announced that as part of its new gene therapy coverage program, Cigna plans to cover Zolgensma for children under the age of 2 with SMA. 

Read more here. 

References

1. Jiang X, Kannan A, Gangwani L. ZPR1-Dependent Neurodegeneration Is Mediated by the JNK Signaling Pathway. J Exp Neurosci. 2019;13:1179069519867915. doi:10.1177/1179069519867915

2. Kariyawasam DST, D’Silva A, Lin C, Ryan MM, Farrar MA. Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy. Front Neurol. 2019;10:898. doi:10.3389/fneur.2019.00898

3. Sandrock AW, Farwell W. Comparisons Between Separately Conducted Clinical Trials: Letter to the Editor Regarding Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, et al. Adv Ther (2019) 36(5):1164-76. doi:10.1007/s12325-019-00923-8. Adv Ther. September 2019. doi:10.1007/s12325-019-01087-1

4. Dabbous O, Maru B, Jansen JP, et al. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019;36(5):1164-1176. doi:10.1007/s12325-019-00923-8

5. Dabbous O, Maru B, Jansen JP, et al. Response to: Alfred Sandrock, Wildon Farwell. Letter to the Editor, Comparisons Between Separately Conducted Clinical Trials: Letter to the Editor Regarding Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, et al. Adv Ther (2019) 36(5):1164-76. doi:10.1007/s12325-019-00923-8. Adv Ther. September 2019. doi:10.1007/s12325-019-01088-0

6. Lempriere S. Alternative gene therapy target identified in spinal muscular atrophy mice. Nat Rev Neurol. September 2019. doi:10.1038/s41582-019-0262-5

7. Forotti G, Nizzardo M, Bucchia M, et al. CSF transplantation of a specific iPSC-derived neural stem cell subpopulation ameliorates the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1. Exp Neurol. 2019;321:113041. doi:10.1016/j.expneurol.2019.113041

8. Pacak CA, Kang PB. The End of the Beginning: The Journey to Molecular Therapies for Spinal Muscular  Atrophy. Pediatr Neurol. August 2019. doi:10.1016/j.pediatrneurol.2019.07.018

9. Mercuri E, Lucibello S, Pera MC, et al. Long-term progression in type II spinal muscular atrophy: A retrospective observational study. Neurology. August 2019. doi:10.1212/WNL.0000000000008166

10. van der Heul AMB, Wijngaarde CA, Wadman RI, et al. Bulbar Problems Self-Reported by Children and Adults with Spinal Muscular Atrophy. J Neuromuscul Dis. August 2019. doi:10.3233/JND-190379

11. Hoot N. Nusinersen for type 1 spinal muscular atrophy: A father’s perspective. Pediatrics. 2019.

12. Morse S. Cigna offers new coverage program for expensive gene therapy. Healthcare Finance. https://www.healthcarefinancenews.com/node/139137. Published 2019. Accessed September 13, 2019.