2019 was a year of significant progress in our understanding of SMA and how to best address it – clinically and otherwise. Below is a roundup of some of the final SMA data shared in late 2019.

Understanding SMA

The classical complement pathway mediates microglia-dependent remodeling of spinal motor circuits during development in SMA.1

This paper describes a study revealing the critical role of a protein, C1q, in the normal refinement of sensory-motor circuits and demonstrating that this protein is specifically implicated in SMA. The authors show that C1q is not only responsible for microglia-mediated elimination in a mouse model of SMA but that inhibiting the protein pharmacologically also rescues dysfunctional synapses. These results point to a potential therapeutic target for those with SMA.

Read more here. 

Lowering EphA4 does not ameliorate disease in a mouse model for severe spinal muscular atrophy.2

In this article, the authors describe their investigation into the therapeutic potential of EphA4, a receptor of the Eph-ephrin system that has been shown to genetically modify ALS in animal models through its effects on axon guidance. Given the similarities between ALS and SMA, it is reasonable to hypothesize that EphA4 could have an impact in SMA. However, the researchers found that lowering EphA4 did not improve motor function or other features of SMA. Though the results suggest that the therapeutic value of lowering EphA4 may be limited in SMA, the authors also highlight the possibility that the severity of disease in their mouse model may have precluded any relevant benefits. More work is therefore needed to elucidate the precise role that EphA4 reduction could play in SMA.

Read more here. 

SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1.3

This paper describes a study into if and how Drosophila may be utilized to investigate pathogenic pathways shared in SMA and ALS. The results both reinforce the relationship between SMA and ALS and point to how the overlapping mechanisms in these diseases can be further explored through genetic studies with Drosophila. Using this model, the authors identified Gemin3, a DEAD box protein that interacts with SMN, as a candidate for impacting the degeneration of motor neurons. 

Read more here.

Diagnostic accuracy of MRI and ultrasound in chronic immune-mediated neuropathies.4

The authors of this study aimed to evaluate the differential value of qualitative and semi quantitative MRI and ultrasound for distinguishing chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) from segmental SMA (sSMA). Based on their results, the authors conclude that from an imaging perspective, ultrasound may provide the most diagnostic value for this type of differential diagnosis.

Read more here.

ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy.5

Based on the therapeutic potential of upregulating the expression of SMN2 in those with SMA, researchers have long been interested in mechanisms by which this expression can be effectively boosted. The authors of this paper describe the way in which zinc finger protein ZPR1 enhances SMN2 expression through its interaction with SMN loci on RNA polymerase II in cells from both animal models of SMA and human SMA patients. They show that overexpressing ZPR1 in preclinical models not only increases levels of SMN but also rescues function and increases lifespan. Based on their results, the authors conclude that ZPR1 is an important target to consider in emerging SMA treatments.

Read more here.

Recent Reviews:

  • JNK signaling pathway involvement in spinal cord neuron development and death.6

In this review, the authors focus on JNK-dependent signaling and its roles in spinal cord function. As part of their discussion, they consider how the signaling pathway could be therapeutically targeted to treat motor neuron diseases like SMA and ALS. 

Read more here.

  • Neurofilament proteins as prognostic biomarkers in neurological disorders.7

Abnormal neurofilament assembly is a feature of infantile SMA. In this review of the role of neurofilaments in neurodegenerative disease, the authors conclude that intermediate filaments may provide promising biomarkers to evaluate disease progression for SMA and other disorders of the nervous system. 

Read more here.

Treating SMA

Simple fluoroscopy-guided transforaminal lumbar puncture: Safety and effectiveness of a coaxial curved-needle technique in patients with spinal muscular atrophy and complex spines.8

The intralaminar approach to administering SMA treatment can be nearly impossible in certain groups of patients. In those with complete interlaminar osseous fusion, the interlaminar lumbar puncture is impossible. This paper describes the authors’ strategy for circumventing this challenge by performing transforaminal lumbar punctures. They report that between October 2017 and November 2018, they performed 59 transforaminal lumbar punctures in 12 patients, with 100 percent technical success. The procedure led to one major and two minor complications. Based on their experience with this approach, the authors conclude that a fluoroscopy-guided curved-needle transforaminal approach is an effective way to puncture the lumbar when administering nusinersen to SMA patients with complete interlaminar osseous fusion.  

Read more here.

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.9

Based on the observation that not all SMA patients respond similarly to the newly approved antisense oligonucleotide drug nusinersen, the authors of this article investigated how adding doses of HDAC inhibitors to antisense oligonucleotide treatment affects SMN2 splicing and SMN protein expression in a mouse model of SMA. The results showed that this combination therapy produced additive effects, suggesting that using both approaches simultaneously may be a promising way to clinically address SMA.

Read more here.

Recent Reviews: 

  • Drug treatment for spinal muscular atrophy type I.10

In this review, authors describe their evaluation of the safety and efficacy of SMA type I drug therapies. Their comprehensive review of the literature showed that compared to those receiving placebo, infants with SMA type 1 who receive intrathecal nusinersen are likely to survive longer and reach certain motor milestones. In addition, adverse events in those receiving nusinersen appear to be no higher than such events in children receiving placebo. Though the authors state that it is unclear whether riluzole impacts patients with SMA type 1, they point to the need for more research to determine the relative advantages of nusinersen and riluzole and the potential value of combining them.

Read more here.

  • Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.11

In this review, the authors cover what is known to date about SMARD1. They discuss advances in our knowledge of the molecular mechanisms underlying the disease as well as therapeutic targets.

Read more here.

SMA Management

Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.12

The authors of this paper investigated which factors were predictive of sitting ability in SMA type 1 patients treated with nusinersen. They found that these patients were more likely to develop the ability to sit if they had a higher baseline motor function or if they had higher levels of improvement in their HINE-2 score after 6 months of nusinersen treatment. Given that the number of SMN2 copies is often considered clinically predictive, it is important to note that it was not predictive in this context. 

Read more here.

Supplementary value of denaturing high performance liquid chromatography for routine prenatal diagnosis of spinal muscular atrophy by multiple ligation-dependent probe amplification.13

The potential to diagnose SMA prenatally has been increasingly recognized. In this paper, the authors explore the relevant potential of combining high performance liquid chromatography (DHPLC) with multiple ligation-dependent probe amplification (MLPA). According to their data from 3 families who gave birth to SMA type 1 children, the authors conclude that DHPLC is effective for screening those who carry SMA mutations and that combining DHPLC with MLPA provides an opportunity to diagnose fetuses at high risk for SMA. 

Patient Focus and Policy Implications

Neuromuscular diseases of the newborn.14

In this review of diagnostic strategies for neonates with peripheral nervous system disorders, the authors emphasize the importance of precise genetic diagnoses, particularly in the context of emerging treatments for diseases like SMA.

Read more here.

References

1. Vukojicic A, Delestree N, Fletcher E V, et al. The Classical Complement Pathway Mediates Microglia-Dependent Remodeling of Spinal Motor Circuits during Development and in SMA. Cell Rep. 2019;29(10):3087-3100.e7. doi:10.1016/j.celrep.2019.11.013

2. Poppe L, Smolders S, Rue L, et al. Lowering EphA4 Does Not Ameliorate Disease in a Mouse Model for Severe Spinal Muscular Atrophy. Front Neurosci. 2019;13:1233. doi:10.3389/fnins.2019.01233

3. Cacciottolo R, Ciantar J, Lanfranco M, et al. SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1. Sci Rep. 2019;9(1):18666. doi:10.1038/s41598-019-53508-4

4. Oudeman J, Eftimov F, Strijkers GJ, et al. Diagnostic accuracy of MRI and ultrasound in chronic immune-mediated neuropathies. Neurology. December 2019. doi:10.1212/WNL.0000000000008697

5. Kannan A, Jiang X, He L, Ahmad S, Gangwani L. ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain. December 2019. doi:10.1093/brain/awz373

6. Schellino R, Boido M, Vercelli A. JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death. Cells. 2019;8(12). doi:10.3390/cells8121576

7. Lee Y, Lee BH, Yip W, Chou P, Yip B-S. Neurofilament proteins as prognostic biomarkers in neurological disorders. Curr Pharm Des. December 2019. doi:10.2174/1381612825666191210154535

8. Jacobson JP, Cristiano BC, Hoss DR. Simple Fluoroscopy-Guided Transforaminal Lumbar Puncture: Safety and Effectiveness of a Coaxial Curved-Needle Technique in Patients with Spinal Muscular Atrophy and Complex Spines. AJNR Am J Neuroradiol. December 2019. doi:10.3174/ajnr.A6351

9. Pagliarini V, Guerra M, Di Rosa V, Compagnucci C, Sette C. 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. J Neurochem. December 2019:e14935. doi:10.1111/jnc.14935

10. Wadman RI, van der Pol WL, Bosboom WM, et al. Drug treatment for spinal muscular atrophy type I. Cochrane database Syst Rev. 2019;12:CD006281. doi:10.1002/14651858.CD006281.pub5

11. Saladini M, Nizzardo M, Govoni A, et al. Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights. J Cell Mol Med. December 2019. doi:10.1111/jcmm.14874

12. Aragon-Gawinska K, Daron A, Ulinici A, et al. Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen. Dev Med Child Neurol. December 2019. doi:10.1111/dmcn.14412

13. Tan Y, Wang H, Zhao T, Cheng M, Zhang C. [Supplementary value of denaturing high performance liquid chromatography for routine prenatal diagnosis of spinal muscular atrophy by multiple ligation-dependent probe amplification]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019;36(12):1175-1178. doi:10.3760/cma.j.issn.1003-9406.2019.12.006

14. Fay AJ. Neuromuscular Diseases of the Newborn. Semin Pediatr Neurol. 2019;32:100771. doi:10.1016/j.spen.2019.08.007