Late-Breaking SMA Treatment Insights You May Have Missed in February

Nisha Cooch, PhD avatar

by Nisha Cooch, PhD |

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February wrapped up with a surge of data on SMA, including novel investigations into how combinatorial therapies may provide new advantages to those with the disease. More information on how nusinersen impacts patients has also become available, as have new findings related to newborn screening and the genetics underlying SMA.

Here is a roundup of some of the latest in SMA research that broke late in February.

Understanding SMA

Polysomnography findings in pediatric spinal muscular atrophy types 1-3.1

This paper describes a study into the sleep architecture and breathing characteristics of children with SMA. The researchers studied 31 children with different SMA types and found that sleep disordered breathing occurred across all types of SMA. Based on their analysis, central sleep apnea was the most common sleep disorder occurring in SMA children with sleep disordered breathing.

Read more here. 

Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models.2

In this paper, researchers describe their analysis of the implications of low SMN levels in SMA. The scientists were specifically interested in whether the paralysis that occurs in SMA occurs as a result of motor neuron dysfunction or broader motor unit defects. For their analysis, they selectively depleted SMN in skeletal muscle and found that the muscle became significantly damaged, and characteristics consistent with SMA emerged. However, once SMN levels were restored, the disease pathology was reversed. Based on their results, the authors argue that treatments that target dysfunctional motor units are needed.

Read more here. 

Analysis of FUSPFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy.3

In this article, researchers describe their study of gene mutations that may modify the severity of SMA. Their results showed that variants of neither plastic 3 (PLS3) nor fused in sarcoma (FUS) modified the severity of SMA at the population level. When investigating variants at the individual level, the authors also failed to identify any variants that reliably correlated with disease severity.

Read more here. 

Transmission characteristics of SMN from 227 spinal muscular atrophy core families in China.4

This paper describes an analysis of the relationship between SMN1 and SMN2 and how these genes vary across generations. The results showed a negative correlation between copy number of SMN1 and SMN2. SMN2 copy number in one generation could also be used to predict SMA disease severity in the children of that generation.

Read the review here. 

Treating SMA

Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy.5

This article describes a study into how the beneficial effects of new SMA therapies may be enhanced through a combinatorial approach. The researchers used a mouse model of SMA and found that myostatin inhibition worked synergistically with SMN-restoring antisense therapy. With this combination therapy, muscle mass improved, body weight increased, and both motor function and physical performance improved. The authors therefore suggest that this type of combinatorial approach should be considered in the treatment of those with SMA.

Read the review here. 

Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on spinal muscular atrophy type 3 patients.6

This paper describes the investigation into the potential of neurofilament concentration in the cerebrospinal fluid to be used as a biomarker to track response to nusinersen treatment in patients with SMA type 3. The researchers looked at the concentration of both heavy chain and light chain phosphorylated neurofilaments before nusinersen treatment and after 6 months of treatment. Neurofilament levels significantly decreased in response to treatment despite motor function only slightly improving in these patients. The authors suggest that reductions in neurofilaments may therefore be a biochemical effect of nusinersen treatment that occurs before changes in motor performance can be observed.

Read the review here. 

Respiratory needs in patients with type 1 spinal muscular atrophy treated with nusinersen.7

This paper describes an investigation into the respiratory effects of nusinersen in patients with SMA type 1. The researchers studied data from 118 children with SMA type 1 before nusinersen treatment, as well as 6 months and 10 months into treatment. They found that more than 80% of the children who were treated with nusinersen before the age of 2 survived and did so without tracheostomy or noninvasive ventilation lasting 16 hours or longer. Respiratory benefits were also observed in older patients. Based on their results, the authors suggest that nusinersen treatment improved not only survival but also respiratory function, especially in children who are younger than 2. 

Read more here.

Recent Review:

  • Engineering adeno-associated virus vectors for gene therapy.8

This review discusses the potential benefits of vector engineering for adeno-associated virus vector-mediated gene delivery for SMA and other conditions. For instance, according to the authors, in addition to optimizing large-scale production of the relevant viruses, vector engineering can also enhance transduction efficiency associated with the virus, increase vector tropism, and circumvent immune response complications. 

Read more here.

Recent Editorial:

  • Combinatorial treatment for spinal muscular atrophy: An Editorial for ‘Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in spinal muscular atrophy cells’ on doi: 10.1111/jnc.14935.9

In this editorial, the authors highlight a study by Pagliarni et al. that used a combination treatment of antisense oligonucleotide treatment and an orally derived histone deacetylase inhibitor in cell models of SMA. By combining these treatment strategies, the researchers were able to overcome limitations associated with single-therapy approaches. The authors argue that the combinatorial approach can now be tested in animal models of SMA and may provide a way to reduce the dose or frequency of antisense oligonucleotide treatment so that intrathecal administration can be limited.

Read the review here. 

Patient Focus and Policy Implications

Newborn screening for spinal muscular atrophy: DNA preparation from dried blood spot and DNA polymerase selection in PCR.10

In this paper, the authors describe an investigation into how to reduce the time required to screen newborns for SMA using polymerase chain reaction (PCR) analysis from DNA derived from dried blood spots on filter papers. As extracting the DNA from dried blood spots is incredibly time consuming, the researchers evaluated a new technique that allows for direct PCR analysis through a punched-out circle of the dried blood spot paper. Given that this new approach sufficiently allowed for the identification of SMA, the authors argue that this approach may provide an easier way to screen newborns for SMA.

Read more here.

Genetic analysis of 90 families affected with spinal muscular atrophy.11

This article describes genetic testing and prenatal diagnosis for 90 families affected by SMA. Multiplex ligation-dependent probe amplification analysis was used for all families, and prenatal diagnosis was undertaken by combining this method with allele-specific PCR. The researchers found that 85 husbands and 88 wives carried heterozygous deletions of exon 7 in the SMN1 gene and that 2 wives with homozygous such deletions were affected. From the standpoint of prenatal diagnosis, 18 fetuses had SMA, 48 were carriers, and 23 were normal. The authors discuss the implications for carrier screening and prenatal diagnosis. 

Read more here.

RESTORE: A prospective multinational registry of patients with genetically confirmed spinal muscular atrophy – Rationale and study design.12

This paper describes RESTORE, a multinational registry that supports the collection and storage of real-world data about the long-term safety and efficacy of SMA interventions. The registry began recruiting SMA patients in September of 2018, and by the start of 2020, had enrolled 64 patients from 25 participating sites. The registry data includes aspects of SMA history and treatment, as well as details related to pulmonary function, nutrition, motor performance, and survival. In addition, quality of life, adverse events, work productivity, healthcare utilization, and caregiver burden are addressed through the registry data. 

Read more here.


1. Chacko A, Sly PD, Gauld L. Polysomnography findings in pediatric spinal muscular atrophy types 1-3. Sleep Med. 2019;68:124-130. doi:10.1016/j.sleep.2019.12.004

2. Kim J-K, Jha NN, Feng Z, et al. Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal  muscular atrophy models. J Clin Invest. February 2020. doi:10.1172/JCI131989

3. Wadman RI, Jansen MD, Curial CAD, et al. Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy. Neurol Genet. 2020;6(1):e386. doi:10.1212/NXG.0000000000000386

4. Cao Y, Qu Y, Bai J, et al. Transmission characteristics of SMN from 227 spinal muscular atrophy core families in China. J Hum Genet. February 2020. doi:10.1038/s10038-020-0730-1

5. Zhou H, Meng J, Malerba A, et al. Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy. J Cachexia Sarcopenia Muscle. February 2020. doi:10.1002/jcsm.12542

6. Faravelli I, Meneri M, Saccomanno D, et al. Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on Spinal Muscular Atrophy type 3 patients. J Cell Mol Med. February 2020. doi:10.1111/jcmm.14939

7. Sansone VA, Pirola A, Albamonte E, et al. Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen. J Pediatr. February 2020. doi:10.1016/j.jpeds.2019.12.047

8. Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. February 2020. doi:10.1038/s41576-019-0205-4

9. Poletti A, Fischbeck KH. Combinatorial treatment for spinal muscular atrophy: An Editorial for ’Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cell. J Neurochem. February 2020. doi:10.1111/jnc.14974

10. Takeuchi A, Tode C, Nishino M, et al. Newborn Screening for Spinal Muscular Atrophy: DNA Preparation from Dried Blood Spot and DNA Polymerase Selection in PCR. Kobe J Med Sci. 2019;65(3):E95-E99.

11. Li T, Lyu X, Xu P, et al. [Genetic analysis of 90 families affected with spinal muscular atrophy]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020;37(2):116-122. doi:10.3760/cma.j.issn.1003-9406.2020.02.004

12. Finkel RS, Day JW, De Vivo DC, et al. RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy – Rationale and Study Design. J Neuromuscul Dis. February 2020. doi:10.3233/JND-190451