The beginning of fall has seen a steady stream of new data elucidating SMA mechanisms, as well as options for managing and treating the disease. There have also been reports of evolving efforts to optimize both SMA research and clinical care, such as through a new SMA registry and the development of new prenatal screening methods. 

News around Novartis’ data manipulation with respect to its SMA drug Zolgensma appears to be slowing down, with the FDA determining that the inaccurate data were related to issues of drug production. The FDA’s conclusion that the manipulation would not affect their view of the efficacy or safety of Zolgensma appears to have softened journalists’ interest in the incident.

Here a roundup of the latest data on SMA.

Understanding SMA

Impaired kidney structure and function in spinal muscular atrophy.1

This article describes a study aimed at characterizing serum profiles and kidney tissues from SMA type 1 patients who died before disease modifying therapies were available to clarify what impact SMA may have on the kidneys. The data show that these SMA patients’ kidneys were impaired, with abnormalities often consistent with renal tubular dysfunction. The authors conclude that more research is needed to help develop strategies for addressing kidney function in patients with SMA.

Read more here. 

iPSC-derived functional human neuromuscular junctions model the pathophysiology of neuromuscular diseases.4

This article describes an approach for modeling SMA pathology related to neuromuscular junction dysfunction. According to the authors, this strategy offers the first reliable way to model this aspect of the disease and should be a valuable tool for further research into neuromuscular junction pathology.

Read more here.

3D Facial morphology in children affected by spinal muscular atrophy type 2 (SMAII).3

To identify specific facial characteristics of patients with SMA type 2, the authors of this study analyzed facial scans from 22 such patients ranging in age from 2 to 7. They identified several facial alterations in these patients and suggest that craniofacial alterations should be assessed in SMA patients, with consideration to how these alterations may impact feeding.

Read more here.

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes.2

In this paper, researches describe the role of VRK1 in the interference of neuromotor development that is observed in SMA. According to the authors, the interference likely occurs because of changes in cellular activity that VRK1 normally regulates. In neuromotor developmental syndromes like SMA, VRK1 appears to be functionally impaired, preventing it from carrying out its normal regulatory functions.

Read more here. 

Cough, sniff and maximal static pressure patterns in spinal muscular atrophy.5

In this short communication, the authors explain their analysis of esogastric pressures that occur when SMA type 2 and SMA type 3 patients voluntarily cough. They undertook this analysis of 49 patients to determine the extent of involvement of the diaphragm, the abdominal muscles, and the intercostal muscles and found that the involvement of these systems varies from patient to patient.  

Read more here.

Recent Review:

  • Astrocytes in Motor Neuron Diseases.6

This review describes SMA and ALS and the role that astrocytes play in the pathogenesis of these diseases. It has been increasingly recognized that in those with SMA and ALS, glia that are situated near motor neurons often contain lesion. The authors posit that glia may provide a valuable new target for therapeutic interventions for SMA and ALS.

Read more here.

Treating SMA

Wrangling RNA: Antisense oligonucleotides for neurological disorders.9

This focus article provides information on the use of antisense oligonucleotides (ASOs) in the treatment of SMA and describes the relevant successes and impact on the SMA field. It also discusses the potential value of ASO treatment for other neuromuscular diseases as well as the technical challenges that will have to be addressed if this type of treatment is to be adequately translated to combat other diseases. 

Read more here.

Better living through peptide-conjugated chemistry: next-generation antisense oligonucleotides.11

Despite the promising results that have been observed with the use of ASOs to treat SMA and Duchenne muscular dystrophy, these therapies are limited by their inability to readily penetrate tissue. This article describes a novel method that has allowed researchers to improve ASO delivery by conjugating ASO with Pip6a, an arginine-rich cell-penetrating peptide. These results point to a strategy for developing new ASOs that could be used to treat other conditions.

Read more here.

Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice.7

This paper describes preclinical research into the potential of implementing fetal gene therapy for diseases like SMA. The researchers found that fetal gene therapy was associated with improvements in number of motor neurons and in muscle pathology. They conclude that fetal gene therapy may offer an alternative therapeutic strategy for addressing SMA.

Read the letter here.

Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen.8

This article describes a study into whether serum neurofilament light chain (NfL) may provide diagnostic or prognostic value in patients with SMA. The researchers monitored NfL levels in 46 patients with SMA over a 14-month period, before and during their treatment with nusinersen. The results were mixed, with better motor performance correlating with lower NfL levels but not with changes in NfL levels. The researchers concluded that more research is needed to determine if monitoring NfL can provide valuable information on the status or evolution of SMA. 

Read the response here. 

Improvement of spinal muscular atrophy via correction of the SMN2 splicing defect by Brucea javanica (L.) Merr. extract and Bruceine D.10

The authors of this study aimed to identify substances from plants that could potentially correct SMN2 splicing and thereby rescue SMA phenotypes. Through the screening of nearly 500 plant extracts and the analysis of SMN2 splicing using a luciferase-based SMN2 splicing reporter and SMN2 mRNA RT-PCR, the authors determined that Brucea javanica extract and a component of it – Bruceine D – can correct SMN2 splicing. The correction in SMN2 splicing was also associated with symptom improvements in an animal model of SMA. The authors therefore conclude that Brucea javanica and Bruceine D may provide new therapeutic candidates for SMA.

Read more here.

Note: Zolgensma data manipulation.19

This Medical Letter addresses data manipulation related to Zolgensma, which has recently been widely covered by journalists. In this letter, the FDA issuance of a statement on the data inaccuracy issues in August is described. The FDA has concluded that the faulty data was related to the drug’s production process and not to safety or efficacy issues with the drug and so alternations to the previous review of the drug are not warranted.

Read more here.

Managing SMA

Abnormal coagulation parameters are a common non-neuromuscular feature in patients with spinal muscular atrophy.12

In this paper, the authors point to evidence that bodily systems beyond the nervous system are impacted in patients with SMA. Here, the researchers demonstrated that patients with SMA commonly have prolonged activated partial thromboplastin time (APTT), regardless of how old they are or how severe their disease is. They also found abnormalities in prothrombin time (PT), platelet count, and the antigen referred to as von Willebrand Factor (vWF). Based on their observations, the authors suggest that these levels should be measured in patients with SMA prior to invasive procedures to reduce risks in this population.

Read more here. 

Multimodal anesthesia management of a morbidly obese spinal muscular atrophy patient with obstructive sleep apnea.13

In this Letter to the Editor, the authors point out that there are currently no guidelines for how to reduce risks associated with anesthesia-related respiratory hypoxia in SMA patients with obstructive sleep apnea who are morbidly obese. To help combat that problem, they offer a discussion of their approach to this challenge in a 27-year old male patient with SMA type 3. 

Read more here. 

Combined noninvasive ventilation and mechanical insufflator-exsufflator for acute respiratory failure in patients with neuromuscular disease: effectiveness and outcome predictors.14

The research described in this paper was undertaken to determine if it may be effective to combine noninvasive ventilation and mechanical insufflator-exsufflator in SMA patients and other neuromuscular disease patients who suffer from acute respiratory failure. The results revealed that combining these methods can provide an efficient way to prevent intubation in this patient population. Additionally, clinical features observed within 8 hours of this combination approach appeared to be predictive of treatment outcomes.

Read more here. 

Exploring spinal muscular atrophy and its impact on functional status: Indian scenario.15

This paper describes a study into what prevents SMA patients from undergoing physiotherapy. Based on the analysis of 90 patients, the authors identified factors including economic constraints, difficulty in traveling, and lack of mobility and family support as reported barriers to pursuing physiotherapy and suggest that these barriers should be addressed.

Read more here. 

Patient Focus and Policy Implications

Development and validation of a haplotype-free technique for non-invasive prenatal diagnosis of spinal muscular atrophy.17

This article describes the development and validation of a non-invasive technique for prenatal screening and diagnosis of SMA. The authors tested the technique on pregnant women containing a single copy of SMN1 and carrying male fetuses. Based on their results, the authors conclude that their approach can be used in the first trimester and that it offers a low-cost and reliable way to identify SMA prenatally.

Read more here. 

Variations in prenatal screening in a US federal healthcare system: Same coverage, different options.16

The authors of this study surveyed all 49 U.S. military treatment facilities offering comprehensive prenatal care to gain an understanding of their methods of screening and to identify differences in practices between these institutions. Their research revealed that at the time of data collection, only 5 of the facilities, or 12% of them, provided SMA carrier screening. The authors suggest that standardized guidance and protocols could improve screening processing and genetic counseling provided by the U.S. military.  

Read more here. 

Development of an academic disease registry for spinal muscular atrophy.18

This article serves to report on a new registry on SMA that is the result of a collaboration between the U.S., U.K., and Italy and supported by advocacy groups and a biotechnology company. The registry has been developed within academic centers to allow for deep phenotyping of all SMA patients and to enable longitudinal studies that can help elucidate the disease and the impact of therapeutics. 

Read more here. 

References

1. Nery FC, Siranosian JJ, Rosales I, et al. Impaired kidney structure and function in spinal muscular atrophy. Neurol Genet. 2019;5(5):e353. doi:10.1212/NXG.0000000000000353

2. Martin-Doncel E, Rojas AM, Cantarero L, Lazo PA. VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes. Sci Rep. 2019;9(1):13381. doi:10.1038/s41598-019-49821-7

3. Pucciarelli V, Gibelli D, Mastella C, et al. 3D Facial morphology in children affected by spinal muscular atrophy type 2 (SMAII). Eur J Orthod. September 2019. doi:10.1093/ejo/cjz071

4. Lin C-Y, Yoshida M, Li L-T, et al. iPSC-derived functional human neuromuscular junctions model the pathophysiology of neuromuscular diseases. JCI insight. 2019;4(18). doi:10.1172/jci.insight.124299

5. Khirani S, Amaddeo A, Fauroux B. Cough, sniff and maximal static pressure patterns in spinal muscular atrophy. Respir Physiol Neurobiol. September 2019:103308. doi:10.1016/j.resp.2019.103308

6. Valori CF, Guidotti G, Brambilla L, Rossi D. Astrocytes in Motor Neuron Diseases. Adv Exp Med Biol. 2019;1175:227-272. doi:10.1007/978-981-13-9913-8_10

7. Rashnonejad A, Amini Chermahini G, Gunduz C, et al. Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice. Mol Ther. August 2019. doi:10.1016/j.ymthe.2019.08.017

8. Wurster CD, Steinacker P, Gunther R, et al. Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J Neurol. September 2019. doi:10.1007/s00415-019-09547-y

9. Talbot K, Wood MJA. Wrangling RNA: Antisense oligonucleotides for neurological disorders. Sci Transl Med. 2019;11(511). doi:10.1126/scitranslmed.aay2069

10. Baek J, Jeong H, Ham Y, et al. Improvement of spinal muscular atrophy via correction of the SMN2 splicing defect by Brucea javanica (L.) Merr. extract and Bruceine D. Phytomedicine. 2019;65:153089. doi:10.1016/j.phymed.2019.153089

11. McNally EM, Leverson BD. Better living through peptide-conjugated chemistry: next-generation antisense oligonucleotides. J Clin Invest. September 2019. doi:10.1172/JCI131933

12. Wijngaarde CA, Huisman A, Wadman RI, et al. Abnormal coagulation parameters are a common non-neuromuscular feature in patients with spinal muscular atrophy. J Neurol Neurosurg Psychiatry. September 2019. doi:10.1136/jnnp-2019-321506

13. Gau T-P, Chen G-Y, Su M-P, Cheng K-I. Multimodal anesthesia management of a morbidly obese spinal muscular atrophy patient with obstructive sleep apnea. Kaohsiung J Med Sci. September 2019. doi:10.1002/kjm2.12131

14. Chen T-H, Liang W-C, Chen I-C, Liu Y-C, Hsu J-H, Jong Y-J. Combined noninvasive ventilation and mechanical insufflator-exsufflator for acute respiratory failure in patients with neuromuscular disease: effectiveness and outcome predictors. Ther Adv Respir Dis. 2019;13:1753466619875928. doi:10.1177/1753466619875928

15. Bose M, Parab SD, Patil SM, Pandey NA, Pednekar G V, Saini SS. Exploring spinal muscular atrophy and its impact on functional status: Indian scenario. Indian J Public Health. 2019;63(3):254-257. doi:10.4103/ijph.IJPH_239_18

16. Thagard AS, Foglia LM, Staat BC, Lutgendorf MA. Variations in prenatal screening in a US federal healthcare system: Same coverage, different options. J Genet Couns. September 2019. doi:10.1002/jgc4.1165

17. Wei X, Lv W, Tan H, Liang D, Wu L. Development and validation of a haplotype-free technique for non-invasive prenatal diagnosis of spinal muscular atrophy. J Clin Lab Anal. September 2019:e23046. doi:10.1002/jcla.23046

18. Mercuri E, Finkel R, Scoto M, et al. Development of an academic disease registry for spinal muscular atrophy. Neuromuscul Disord. August 2019. doi:10.1016/j.nmd.2019.08.014

19. Note: Zolgensma data manipulation. Med Lett Drugs Ther. 2019;61(1579):129.