In July, the literature pertaining to spinal muscular atrophy (SMA) has focused mainly on understanding the disease. Information on treatments has been published largely in review form, while there has also been some new information on managing the disease and what having the disease means for patients. 

Here is a roundup of SMA data published over the last couple of weeks.

Understanding SMA

Muscle fiber-type selective propensity to pathology in the nmd mouse model of SMARD1.1 

This paper provides data on muscle fiber denervation in a mouse model of spinal muscular atrophy with respiratory distress type 1 (SMARD1). The researchers found that denervation vulnerability is associated with loss and atrophy of certain muscle fiber types, including the myosin heavy chain isoforms MyHC-IIb and MyHC-IIx. However, this vulnerability was also shown to be associated with increased muscle fiber in MyHC-I and MyHC-IIa, which likely reflects compensation for lost muscle. This observed selective vulnerability to muscle denervation provides new information that may be useful in the development of therapeutic interventions. 

Read more here. 

A spinal muscular atrophy family with intrafamilial phenotype differences despite the same copy-number variation in SMN2.2

In this editorial, the authors describe a case study of a brother and sister in a family with SMA. Despite each having 4 copies of the survival motor neuron 2 (SMN2) gene, the male has a significantly more severe phenotype than his sister. These results support the notion that sex may affect SMA phenotypes. 

Read more here. 

Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy.3

This study shows the utility of magnetic resonance neurography (MRN) in quantitatively distinguishing peripheral nerve lesions in 5q-linked SMA types 2, 3a, and 3b. The results suggest that quantitative MRN may provide a new biomarker for SMA that could improve our ability to observe early responses to potential treatments.

Read more here.

Pathologic alterations in the proteome of synaptosomes from a mouse model of spinal muscular atrophy.4

The authors of this article provide information on the proteome dynamics of central synapses in a model of SMA. Specifically, the authors identified 65 alterations that occur in early onset SMA that point to dysregulation in mitochondrial processes as well as in cholesterol biogenesis and protein clearance. This new information may provide fruitful information for therapeutic targets aimed at stabilizing central synapses in those with SMA.

Read more here. 

Functional characterization of SMN evolution in mouse models of SMA.5

By delivering SMN homologues via an adeno-associated virus serotype 9 (AAV9) vector to an animal model of SMA, the authors of this study identified a conserved region of RNA that is associated with the SMA phenotype across species. However, the researchers state that because the intervention did not fully rescue animals, more sequences need to be identified to understand the full SMA pathology. 

Read more here. 

Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling.6

In this article, the authors discuss their investigation into potential role of the c-Jun NH2-terminal kinase (JNK) molecular pathways in the death of motor neurons that occurs in SMA. Though motor neurons do not appear to undergo stress-activated JNK-c-Jun signaling in SMA, this signaling appears to be important for normal development of motor neurons. The authors therefore recommend caution in using JNK antagonists in those with SMA.

Read more here. 

Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy.7

This article describes an investigation into the role of the p53 signaling pathway in the motor unit degeneration that is observed in SMA. According to the data, increases in p53-related transcripts at the cell body are associated with the onset of pathology at the neuromuscular junctions and so supports the notion that p53 is an effector of degeneration of axons and synapses.

Read more here. 

Applying deep neural network analysis to high-content image-based assays.8

This article provides new information on how deep neural network analysis can be used to identify SMA. Using a combination of imaging studies and machine learning, the researchers exposed primary skin fibroblasts from 12 SMA patients and 12 healthy controls to a convolutional neural network (CNN). After this exposure, the CNN was able to accurately differentiate between primary skin fibroblasts from these two populations. These results suggest that innovative technologies may be able to help us better understand and identify diseases that have complex genetic dynamics.  

Read more here. 

Treating SMA

Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.9

This article examines the effects of the gene therapy, onasemnogene abeparvovec (AVXS-101), on infants with SMA type 1. According to the data collected on 12 infants with the disease, unassisted sitting occurred earlier in infants given early dosing (before the age of 3 months) than in those given later dosing. The authors state that these results support the value of newborn screening and early intervention. They also argue that AVXS-101 may help patients regardless of their pretreatment motor function.

Read more here.

Nusinersen helps restore walking ability in childhood spinal muscular atrophy.10

In this clinical note, the authors describe the case of a boy diagnosed with an intermediate form of SMA type 2 and SMA type 3a who lost the ability to walk around the age of 2. At age 3, he was started on nusinersen, and regained the ability to walk independently after 2 weeks of treatment. The time he needed to stand up from a seated position also decreased from over 10 seconds to between 6 and 7 seconds. He experienced no adverse side effects. These results suggest that nusinersen may provide benefits when SMA patients still have some remaining motor neurons.

Read more here.

Nusinersen improves walking distances and reduces fatigue in later-onset SMA.11

The impact of nusinersen on walking distance in patients with later-onset SMA was the focus of this article. The study involved 14 children with SMA type 2 or SMA type 3 who performed the 6-Minute Walk Test (6MWT) before and after receiving a dose of nusinersen. Nusinersen improved motor function in these children, including increasing how far they could walk and how long it took for them to fatigue. 

Read more here.

Recent Reviews:

  • Onasemnogene Abeparvovec: First global approval.12

This review covers AVXS-101, which in May of this year became the first gene therapy in the U.S. to be approved for the treatment of SMA. It is an AAV-based gene therapy. This therapy is delivered to motor neuron cells of SMA patients to provide them with a functional copy SMN.

Read the review here. 

  • Antisense therapies for movement disorders.13

In this review, the authors cover the details of antisense oligonucleotides and their therapeutic potential in movement disorders including SMA and Duchenne muscular dystrophy.

Read the review here. 

  • Antisense oligonucleotide therapies for neurodegenerative diseases.14

This review highlights successes from the antisense oligonucleotide therapy nusinersen and suggests that the information gathered through the use of this therapy is likely to help in the development and optimization of other antisense drugs to treat diseases of the nervous system.

Read the review here. 

  • Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate.15

This review covers aspects of the use of olesoxime for a variety of diseases including SMA and provides suggestions on how this drug may be further used to combat neurodegenerative diseases. Olesoxime is a cholesterol derivative that targets the mitochondria and has been shown to provide motor symptom benefits over 12 months of treatment in SMA patients. 

Read the review here. 

  • Gene therapies for neuromuscular diseases.16

This review provides a comprehensive overview of gene therapy and how it is currently being applied to certain diseases including SMA. The authors call for more research to help determine the long-term safety and efficacies of gene therapy options.

Read the review here. 

Managing SMA

Evolution of bone mineral density, bone metabolism and fragility fractures in Spinal Muscular Atrophy (SMA) types 2 and 3.17

In this study, the bones of 32 SMA patients were evaluated. Patients had bone resorption markers that were higher than normal, suggesting that SMA increases vulnerability to bone fragility. These results were based on assessments of bone metabolism, bone mineral density, and bone fractures.

Read more here. 

Patients with spinal muscular atrophy use high percentages of trunk muscle capacity to perform seated tasks.18

To investigate trunk function in patients with SMA type 2 and SMA type 3, the authors of this study had 17 SMA patients and 15 healthy controls perform upper extremity tasks while seated. They found that those with SMA had weaker trunks compared to controls. Specifically, those with SMA had a lower trunk torque and a narrower active range of motion. The authors state that because those with SMA use higher percentages of their trunk muscle capacity to perform tasks, they are vulnerable to muscle fatigue, which clinicians should consider while managing these patients.

Read more here. 

The complex spine in children with spinal muscular atrophy: The tranforaminal approach – a transformative technique.19

Here, the authors provide information on intrathecal nusinersen injections in patients with SMA type 1, SMA type 2, and SMA type3. While the injections used in this study were successful in patients with both simple and complex spines, the results suggest that injections for those with simple spines likely do not require imaging assistance. On the other hand, those with complex spines may need to undergo imaging during injection route planning and to guide the injections themselves. 

Read more here. 

Patient Focus and Policy Implications

Recent Review:

  • Spinal muscular dystrophy – a revisit of the diagnosis and treatment modalities.20

This review focuses on differences in clinical features of SMA and how innovation is spurring molecular diagnosis of the disease. The authors encourage physicians and others in the healthcare community stay abreast of changes in SMA detection and treatment. 

Read more here.

News

Governor Lamont signs bill mandating newborn spinal screening.21

Governor Ned Lamont of Connecticut has signed a bill that will require Connecticut hospitals to test newborns for SMA beginning in 2020. Parents with religious objections will be able to opt out of the screening. 

Read more here.

References

1. Villalon E, Lee NN, Marquez J, Lorson CL. Muscle fiber-type selective propensity to pathology in the nmd mouse model of SMARD1. Biochem Biophys Res Commun. 2019;516(1):313-319. doi:10.1016/j.bbrc.2019.06.117

2. Park JM, Nishio H, Shin JH, Park JS. A Spinal Muscular Atrophy Family with Intrafamilial Phenotype Differences Despite the Same Copy-Number Variation in SMN2. J Clin Neurol. 2019;15(3):395-397. doi:10.3988/jcn.2019.15.3.395

3. Kollmer J, Hilgenfeld T, Ziegler A, et al. Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy. Neurology. July 2019. doi:10.1212/WNL.0000000000007945

4. Eshraghi M, Gombar R, De Repentigny Y, Vacratsis PO, Kothary R. Pathologic Alterations in the Proteome of Synaptosomes from a Mouse Model of Spinal Muscular Atrophy. J Proteome Res. July 2019. doi:10.1021/acs.jproteome.9b00159

5. Osman EY, Bolding MR, Villalon E, et al. Functional characterization of SMN evolution in mouse models of SMA. Sci Rep. 2019;9(1):9472. doi:10.1038/s41598-019-45822-8

6. Pilato CM, Park JH, Kong L, et al. Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun  signaling. Hum Mol Genet. July 2019. doi:10.1093/hmg/ddz150

7. Courtney NL, Mole AJ, Thomson AK, Murray LM. Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy. Cell Death Dis. 2019;10(7):515. doi:10.1038/s41419-019-1727-6

8. Yang SJ, Lipnick SL, Makhortova NR, et al. Applying Deep Neural Network Analysis to High-Content Image-Based Assays. SLAS Discov  Adv life Sci R D. July 2019:2472555219857715. doi:10.1177/2472555219857715

9. Lowes LP, Alfano LN, Arnold WD, et al. Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatr Neurol. May 2019. doi:10.1016/j.pediatrneurol.2019.05.005

10. Sugimoto M, Aiba K, Koyama N, Yokochi K, Nishio H. Nusinersen helps restore walking ability in childhood spinal muscular atrophy. Pediatr Int. July 2019. doi:10.1111/ped.13867

11. Montes J, Dunaway Young S, Mazzone ES, et al. Nusinersen Improves Walking Distance and Reduces Fatigue in Later-Onset SMA. Muscle Nerve. July 2019. doi:10.1002/mus.26633

12. Hoy SM. Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019;79(11):1255-1262. doi:10.1007/s40265-019-01162-5

13. Scoles DR, Pulst SM. Antisense therapies for movement disorders. Mov Disord. July 2019. doi:10.1002/mds.27782

14. Bennett CF, Krainer AR, Cleveland DW. Antisense Oligonucleotide Therapies for Neurodegenerative Diseases. Annu Rev Neurosci. 2019;42:385-406. doi:10.1146/annurev-neuro-070918-050501

15. Weber JJ, Clemensson LE, Schioth HB, Nguyen HP. Olesoxime in Neurodegenerative Diseases: Scrutinising a Promising Drug Candidate. Biochem Pharmacol. July 2019. doi:10.1016/j.bcp.2019.07.002

16. Saffari A, Weiler M, Hoffmann GF, Ziegler A. [Gene therapies for neuromuscular diseases]. Nervenarzt. July 2019. doi:10.1007/s00115-019-0761-z

17. Baranello G, Vai S, Broggi F, et al. Evolution of bone mineral density, bone metabolism and fragility fractures in Spinal Muscular Atrophy (SMA) types 2 and 3. Neuromuscul Disord. June 2019. doi:10.1016/j.nmd.2019.06.001

18. Peeters LHC, Janssen MMHP, Kingma I, van Dieen JH, de Groot IJM. Patients with spinal muscular atrophy use high percentages of trunk muscle capacity to perform seated tasks. Am J Phys Med Rehabil. July 2019. doi:10.1097/PHM.0000000000001258

19. Towbin R, Schaefer C, Kaye R, Abruzzo T, Aria DJ. The Complex Spine in Children with Spinal Muscular Atrophy: The Transforaminal Approach-A Transformative Technique. AJNR Am J Neuroradiol. July 2019. doi:10.3174/ajnr.A6131

20. Srivastava G, Srivastava P. Spinal muscular dystrophy – a revisit of the diagnosis and treatment modalities. Int J Neurosci. July 2019:1-16. doi:10.1080/00207454.2019.1635128

21. II HR. Governor Lamont signs bill mandating newborn spinal screening. wtnh.com. https://www.wtnh.com/news/connecticut/governor-lamont-signs-bill-mandating-newborn-spinal-screening/. Published 2019. Accessed July 14, 2019.