Regulators continue to review SMA drugs and consider policies related to newborn screening while new data emerge related to the mechanisms underlying the disease, as well as those concerning management and treatment. 

Here is a roundup of some of the latest news and research related to SMA.

Understanding SMA

A role for spinal cord hypoxia in neurodegeneration.1

This new piece highlights the role of the vascular system of the spinal cord in SMA. According to the authors, it is critical that we gain a better understanding of chronic hypoxia in neurodegenerative disorders like SMA.

Read more here. 

Analysis of spinal muscular atrophy-like patients by targeted resequencing.2

This paper describes a study aimed at genetically differentiating patients with SMA from those who have SMA-like symptoms. The authors evaluated patients with lower motor neuron symptoms using targeted resequencing with next generation sequencing (NGS) technology. With this method, the authors identified new causative variants in three patients, suggesting that targeted sequencing through NGS is an effective approach for differential genetic diagnosis in this context.

Read more here. 

Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy.3

In this review, the authors use motor neurons as a model to address the questions of how neurons establish specific identities within the nervous system and why certain cell subtypes are specifically vulnerable to neurodegenerative disease. According to the authors, regulatory microRNAs likely play a role in these characteristics of motor neurons. The authors therefore suggest that microRNAs may present an important opportunity for clinical evaluation of SMA.

Read more here.

Recent Review:

  • Spinal muscular atrophy.5

In this newly updated Gene Reviews piece on SMA, the authors cover the latest in SMA clinical characteristics, diagnosis, management, and genetic counseling.

Read more here.

Treating SMA

Nusinersen administration via an intrathecal port in a 16-year-old spinal muscular atrophy patient with profound scoliosis.6

This case study describes an approach for administering nusinersen in SMA type 2 patients with severe scoliosis. The authors describe a girl with this form of SMA who underwent spondylodesis of segments TH7-S1 at the age of 14 due to severe scoliosis. When she was referred for nusinersen therapy, the authors successfully delivered an initial dose via an image-guided spinal tap under sedation. 

Despite success with the first dose, severe scoliotic spinal deformation prevented the subsequent dose. To enable the patient to receive more nusinersen, the authors performed microsurgical hemilaminectomy L4 to implant an intrathecal port catheter. They were then able to effectively deliver the drug, which led them to conclude that this type of implantation in patients with SMA and severe scoliosis is a safe and feasible way to allow for nusinersen therapy while also minimizing radiation exposure and sedation.

Read more here.

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.7

The authors of this paper argue that because of the emergence of new disease-altering therapies for SMA, it is important to have a deeper understanding of the utility of potential outcome measures. Based on this view, they investigated 2 specific outcome measures for SMA: maximal voluntary isometric contraction testing (MVICT) and the six-minute walk test (6MWT), looking at their test-retest reliability and correlation to other outcomes and potential biomarkers.

They found that both tests had good test-retest reliability and correlation with the SMA-functional rating scale, lean muscle mass, and ulnar-CMAP, with MVICT performing slightly better in these areas. Based on these findings, the authors conclude that though MVICT may be preferable, both of these tests are valuable for use in ambulatory adults with SMA.

Read more here.

Treatment with nusinersen – Challenges regarding the indication for children with SMA type 1.8

This piece provides information on how child neurologists from Germany, Austria, and Switzerland used specific clinical details to approach nusinersen treatment in children with SMA type 1. The goal of the authors is to help educate healthcare providers on how to best use what is now known about SMA and relevant therapies to advise patients and families. 

Read more here.

Estimation of the quality of life benefits associated with treatment for spinal muscular atrophy.9

This paper describes a study into estimating quality of life in SMA. The study led to data with face validity for understanding the burden of SMA type 1 and SMA type 2, which the authors suggest should be useful for cost -effectiveness analyses to evaluate therapeutic interventions for SMA.

Read more here.

A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy.10

This article addresses the practical limitations of implementing nusinersen treatment for SMA in the healthcare setting. The authors initiated a retrospective cohort study focused on data from a tertiary care children’s hospital. Based on their findings, they provide recommendations for how to safely and effectively implement nusinersen.

Read more here.

Managing SMA

Patient-reported prevalence of non-motor symptoms in low in adult patients suffering from 5q spinal muscular atrophy.11

This paper describes an investigation into non-motor symptoms in adults with SMA type 2 and type 3. According to the collected data, these patients do not report non-motor symptoms (including psychiatric symptoms) any more frequently than do healthy controls. The presence of non-motor symptoms in SMA patients also did not appear to be indicative of disease severity.

SMA patients did report swallowing difficulties, falling, and leg swelling more often than healthy controls. However, the authors emphasize that adult SMA patients do not appear to be at a heightened risk for depression compared to the general population.

Read more here. 

Expert consensus for early onset scoliosis surgery.12

This paper describes a survey study into how to approach scoliosis surgery in conditions including SMA. The collected data demonstrated no consensus amongst early-onset scoliosis surgeons, though the closest to consensus occurred in the case of SMA. The authors argue that more effort must be focused on the development of evidence-based best practices and guidelines for this type of surgery. 

Read more here.

Patient Focus and Policy Implications

Drugs, genes and screens: The ethics of preventing and treating spinal muscular atrophy.13

This paper involves a discussion on how to ethically approach SMA screening, diagnosis, and treatment in light of advances in our capabilities in these areas. The authors argue that there are moral reasons to prioritize ex-ante methods – or those such as carrier screening, prenatal testing, and gene editing – over ex-post methods that focus on treating the diseases with strategies such as pharmaceutical drugs and gene therapy.

Read more here.

News

  • Colorado has added SMA to its newborn screening tests, which will take effect on the first day of 2020. Read more here. 
  • FDA has granted priority review to the SMA drug risdiplam, which could potentially compete against Spinraza (nusinersen) and Zolgensma (onasemnogene abeparvovec). The decision should be made by the end of May. Read more here. 

References

1. Hernandez-Gerez E, Fleming IN, Parson SH. A role for spinal cord hypoxia in neurodegeneration. Cell Death Dis. 2019;10(11):861. doi:10.1038/s41419-019-2104-1

2. Hosokawa S, Kubo Y, Arakawa R, Takashima H, Saito K. Analysis of spinal muscular atrophy-like patients by targeted resequencing. Brain Dev. November 2019. doi:10.1016/j.braindev.2019.10.008

3. Chen T-H, Chen J-A. Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy. Elife. 2019;8. doi:10.7554/eLife.50848

4. Saugier-Veber P, Marguet F, Vezain M, et al. Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B. Eur J Med Genet. November 2019:103814. doi:10.1016/j.ejmg.2019.103814

5. Prior TW, Finanger E, Leach ME. Spinal Muscular Atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. Seattle (WA); 1993.

6. Flotats-Bastardas M, Linsler S, Zemlin M, Meyer S. Nusinersen Administration Via an Intrathecal Port in a 16-Year-Old Spinal Muscular Atrophy Patient with Profound Scoliosis. Pediatr Neurosurg. November 2019:1-4. doi:10.1159/000504058

7. Elsheikh B, King W, Peng J, et al. Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy. Muscle Nerve. November 2019. doi:10.1002/mus.26756

8. Pechmann A, Baumann M, Bernert G, et al. Treatment with Nusinersen – Challenges Regarding the Indication for Children with SMA Type 1. J Neuromuscul Dis. November 2019. doi:10.3233/JND-190441

9. Lloyd AJ, Thompson R, Gallop K, Teynor M. Estimation Of The Quality Of Life Benefits Associated With Treatment For Spinal Muscular Atrophy. Clinicoecon Outcomes Res. 2019;11:615-622. doi:10.2147/CEOR.S214084

10. Zingariello CD, Brandsema J, Drum E, et al. A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy. Neurol Clin Pract. 2019;9(5):424-432. doi:10.1212/CPJ.0000000000000718

11. Gunther R, Wurster CD, Cordts I, et al. Patient-Reported Prevalence of Non-motor Symptoms Is Low in Adult Patients Suffering From 5q Spinal Muscular Atrophy. Front Neurol. 2019;10:1098. doi:10.3389/fneur.2019.01098

12. Hughes MS, Swarup I, Makarewich CA, et al. Expert Consensus for Early Onset Scoliosis Surgery. J Pediatr Orthop. November 2019. doi:10.1097/BPO.0000000000001473

13. Gyngell C, Stark Z, Savulescu J. Drugs, genes and screens: The ethics of preventing and treating spinal muscular atrophy. Bioethics. November 2019. doi:10.1111/bioe.12695