Data on SMA continue to roll out. This month has shown a growing focus and understanding on issues related to nusinersen as well as newborn screening for SMA across the globe. In addition, more preclinical and translation results have been published. 

Below is the latest in SMA news and research.

Understanding SMA

Low fat diets increase survival of a mouse model of spinal muscular atrophy.3

Based on recent revelations that SMA increases the likelihood of liver complications, the authors of this study used a mouse model of SMA to determine if a low-fat diet may impact the development of liver damage. Their findings showed that low-fat diets led not only to lower levels of ketones and liver damage but also lengthened survival. The authors conclude that these promising preclinical results warrant controlled clinical trials to determine the potential benefits of low-fat diets in SMA patients. 

Read more here.

Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.1

In this article, the authors describe a new mouse model that they have developed to study SMA with respiratory distress type 1 (SMARD1). The previously used mouse model was associated with survival variations that complicated its use, so this new model was created as a way to circumvent those limitations and improve our ability to monitor the influence of new therapeutics on SMARD1.

Read more here. 

PLS3 overexpression delays ataxia in Chp1 mutant mice.2

This article describes a study into potential for plastin 3 (PLS3) to interact with calcineurin like EF-hand protein 1 (CHP1) and influence the development of ataxia and SMA. The results showed that PLS3 is indeed a cross-disease genetic modifier that interacts with CHP1 in a calcium-independent way and can act as a protector against neurodegeneration, delaying ataxia. 

Read more here.

Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy.4

Though SMA is generally viewed as a disease of motor neurons, recent evidence has suggested that muscle may also be directly affected by low levels of the survival motor neuron (SMN) protein. This article describes a study using a mouse model of SMA that found that the muscle in these animals contained reduced levels of a protein that regulates neuronal protein synthesis of SMN through the mTOR pathway. The authors suggest that dysregulation of this pathway may contribute to SMA pathophysiology. 

Read more here. 

Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy.5

In this article, the authors describe their study into the utility of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in evaluating cervical spinal cord and peripheral nerve root changes in SMA patients.  The results showed that the experimenters’ MRI protocol, which involved 4 sequences of investigation with a 3 Tesla MRI system, provided valuable information on mechanisms of SMA. The authors therefore conclude that this technique could be useful for assessing disease progression and response to treatment in SMA patients. 

Read more here.

Treating SMA

Treating neonatal spinal muscular atrophy: A 21st century success story?7

In this piece, the author discusses the genetic advances that have allowed for tailored therapies for SMA and how these therapeutic interventions have impacted SMA patients and the care they receive. Given the observations that early diagnosis and intervention lead to better outcomes, the author argues that more awareness is needed to ensure expeditious diagnosis of SMA which may include changes to newborn screening.

Read more here.

Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3 – A prospective observational study.6

This prospective observational study found for the first time a mild treatment effect in adults with SMA 3. The relevant patient population was treated with nusinersen for 10 months. 

Read more here.

Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: Transforaminal versus conventional approach.8

This article addresses the challenge of intrathecal delivery of nusinersen in SMA patients with spinal deformities or who have undergone surgical correction for scoliosis. The researchers used CT-guidance to deliver nusinersen with a transforaminal approach in 7 patients and the conventional interlaminar approach in 5 patients. All but 47 injections were successful. However, while the conventional approach was associated with only 1 adverse event, the transforaminal approach led to 4 adverse events, 1 of which was a subarachnoid hemorrhage. The researchers conclude that the transforaminal approach is therefore feasible for the delivery of nusinersen but could potentially lead to serious adverse events.

Read the letter here. 

Industry update for May 2019.9

This roundup on pharmaceutical news from May of this year focused largely on advancements in gene therapy. According to the roundup, the FDA approval of Zolgensma was the largest relevant achievement. The article discusses both the promise of and debate around the drug.

Read the response here. 

Systematic approach to developing splice modulating antisense oligonucleotides.10

Based on an evaluation of more than 5,000 antisense oligonucleotides, this piece provides guidelines for how best to design, assess, and optimize splice switching antisense oligomers in vitro. 

Read more here.

Mechanisms of neuronal alternative splicing and strategies for therapeutic interventions.11

This article reviews innovations and insights regarding the mechanisms of alternative splicing in brain cells. The authors focus on providing information on how to mobilize new data to develop therapies that can control or correct defects in splicing.

Read more here.

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging.12

This paper describes findings from a multimodal imaging study into the mechanisms underlying the effects of intrathecal antisense oligonucleotides in SMA. The authors discuss their findings related to the distribution of the antisense oligonucleotides within the CNS, clearance of the drug, and efficacy based on dosage.

Read more here.

Managing SMA

Preimplantation genetic testing for monogenic disease of spinal muscular atrophy by multiple displacement amplification: 11 unaffected livebirths.13

Genetic testing for monogenic disease before implantation has recently become an effective strategy for avoiding SMA in parents who at risk for having a baby with SMA. However, there is little genetic material available for this type of preimplantation testing. In this paper, the authors discuss a study into the impact of multiple displacement amplification as a way to overcome this limitation. When combined with haplotype analysis and mutation amplification, this approach improved the efficiency of PCR and reduced average allele drop-out rates. The authors therefore suggest that specific multiple displacement amplification protocols may help to improve the accuracy of preimplantation genetic testing for monogenic disease for SMA families.

Read more here. 

Clinical characteristics of non-invasive ventilation treatment in children with spinal muscular atrophy and sleep disordered breathing.14

This article describes a study investigating the impacts of non-invasive ventilation used in SMA children who have sleep-disordered breathing. Based on their analysis of 17 cases, the authors concluded that this treatment strategy is not only efficient but may also minimize respiratory tract infection incidence in SMA children.

Read more here. 

Patient Focus and Policy Implications

One year of newborn screening for SMA – Results of a German pilot project.16

This article describes the investigation into how newborn screening affected the clinical course of SMA in over 165,000 children in Germany. Based on their evaluation of newborn screening and early identification of SMA, the authors conclude that this newborn screening should be introduced in all countries due to its ability to improve outcomes in children with SMA. They also point to the need to consider immediate treatment in those with 4 copies of SMN2.

Read more here. 

Heritable genome editing: Who speaks for “future” children?17

The authors of this piece point to the fact that roughly 80% of rare conditions affect children who are unable to make health choices or affect policies and suggest that a moratorium on clinical applications of heritable genome editing fails to consider the rights and preferences of these children.

Read more here. 

The implementation of newborn screening for spinal muscular atrophy: the Australian experience.18

This article provides an analysis of the first year of a statewide newborn screening program for SMA in Australia. In its first year, the program led to the screening of nearly 104,000 newborns and facilitated the implementation of a care plan within an average of 26.5 days. The authors conclude that newborn screening is important for early diagnosis and the clinical benefits it affords.

Read more here. 

References

1. Shababi M, Smith CE, Kacher M, et al. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd. Biochem Biophys Res Commun. October 2019. doi:10.1016/j.bbrc.2019.10.032

2. Janzen E, Wolff L, Mendoza-Ferreira N, et al. PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice. Front Neurosci. 2019;13:993. doi:10.3389/fnins.2019.00993

3. Deguise M-O, Chehade L, Tierney A, Beauvais A, Kothary R. Low fat diets increase survival of a mouse model of spinal muscular atrophy. Ann Clin Transl Neurol. October 2019. doi:10.1002/acn3.50920

4. Rehorst WA, Thelen MP, Nolte H, et al. Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy. Acta Neuropathol Commun. 2019;7(1):154. doi:10.1186/s40478-019-0806-3

5. Stam M, Haakma W, Kuster L, et al. Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy. NeuroImage Clin. 2019;24:102002. doi:10.1016/j.nicl.2019.102002

6. Walter MC, Wenninger S, Thiele S, et al. Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 –  A Prospective Observational Study. J Neuromuscul Dis. September 2019. doi:10.3233/JND-190416

7. Tizzano EF. Treating neonatal spinal muscular atrophy: A 21st century success story? Early Hum Dev. October 2019:104851. doi:10.1016/j.earlhumdev.2019.104851

8. Bortolani S, Stura G, Ventilii G, et al. Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: Transforaminal versus conventional approach. Neuromuscul Disord. August 2019. doi:10.1016/j.nmd.2019.08.007

9. Rosenmayr-Templeton L. Industry update for May 2019. Ther Deliv. October 2019. doi:10.4155/tde-2019-0043

10. Aung-Htut MT, McIntosh CS, Ham KA, et al. Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides. Int J Mol Sci. 2019;20(20). doi:10.3390/ijms20205030

11. Lopez Soto EJ, Gandal MJ, Gonatopoulos-Pournatzis T, Heller EA, Luo D, Zheng S. Mechanisms of Neuronal Alternative Splicing and Strategies for Therapeutic Interventions. J Neurosci. 2019;39(42):8193-8199. doi:10.1523/JNEUROSCI.1149-19.2019

12. Mazur C, Powers B, Zasadny K, et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI insight. 2019;4(20). doi:10.1172/jci.insight.129240

13. Fu Y, Shen X, Wu H, Chen D, Zhou C. Preimplantation Genetic Testing for Monogenic Disease of Spinal Muscular Atrophy  by Multiple Displacement Amplification: 11 unaffected livebirths. Int J Med Sci. 2019;16(9):1313-1319. doi:10.7150/ijms.32319

14. Guo WH, Cao L, Chang L. [Clinical characteristics of non-invasive ventilation treatment in children with  spinal muscular atrophy and sleep disordered breathing]. Zhonghua er ke za zhi = Chinese J Pediatr. 2019;57(10):792-796. doi:10.3760/cma.j.issn.0578-1310.2019.10.012

15. Alves CRR. Exercise training: Thinking ahead to counteract systemic manifestations of spinal muscular atrophy. J Physiol. October 2019. doi:10.1113/JP279033

16. Vill K, Kolbel H, Schwartz O, et al. One year of newborn screening for SMA – Results of a German pilot project. J Neuromuscul Dis. September 2019. doi:10.3233/JND-190428

17. Knoppers BM, Kleiderman E. Heritable Genome Editing: Who Speaks for “Future” Children? Cris J. 2019;2(5):285-292. doi:10.1089/crispr.2019.0019

18. Kariyawasam DST, Russell JS, Wiley V, Alexander IE, Farrar MA. The implementation of newborn screening for spinal muscular atrophy: the Australian experience. Genet Med. October 2019. doi:10.1038/s41436-019-0673-0