Over the past couple of weeks, there have been several new publications regarding spinal muscular atrophy (SMA) treatment. There has also been continued work in the basic science that aims to provide more understanding of the disease as well as research providing information relevant for the management of SMA. 

Here is a roundup of the most recent SMA literature pertaining to treatment of the disease.

Treating SMA

NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorate spinal muscular atrophy in mice.3 

This article expands on recent research that showed that reduced expression of neurocalcin delta (NCALD) behaved protectively in asymptomatic people with SMN1 deletions. This new research investigated the effects of combining NCALD with different forms of antisense oligonucleotides (ASOs) in a mouse model of severe SMA. The scientists tested 450 NCALD ASOs and identified one – ASO3 – as non-toxic and more effective than the other combinations of NCALD and ASOs. The results suggest that combining SMN-dependent therapies like NCALD with SMN-independent ASO-based therapies may provide a way to improve treatment of SMA patients.

Read more here.

Nusinersen in type 1 spinal muscular atrophy: 12-month real world data.4

In this article, data from a 12-month study on the effects of nusinersen on 85 SMA type 1 patients ranging in age from 2 months to nearly 16 years are described. The children who were given nusinersen treatment were assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). This study provides information on the impacts of nusinersen on a wider age range and disease severity than does the ENDEAR study. 

Read more here. (need full text to understand context)

Salbutamol tolerability and efficacy in patients with spinal muscular atrophy.5 

The impact of salbutamol on 48 SMA type 2 patients not taking any other medication are described in this article. According to this 18-month investigation, the drug was associated with subjective positive effects, and it also appeared to benefit children under the age of 6 in terms of motor function. Salbutamol also caused no serious side effects.

Read more here.

Recent Reviews:

  • AAV9 vector: a novel modality in gene therapy for spinal muscular atrophy.6

This review describes the start and evolution of gene therapy research for SMA, culminating in a recent clinical trial where the SMN gene was administered one time via an AAV9 vector in SMA patients. The result was improved motor functioning and longer survival rates. 

Read the review here. 

  • Genetic approaches to the treatment of inherited neuromuscular diseases.7

In this review, the authors cover research related to genetic therapies for neuromuscular diseases including SMA, spinal and bulbar muscular atrophy (SBMA), and Charcot-Marie-Tooth disease. In addition to the progress that has been made in genetic therapies for these diseases, the review also includes considerations on the limitations of the current approaches. 

Read the review here. 

  • New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges.8

The authors of this review discuss progress, opportunities, challenges, and limitations of current pharmacotherapy interventions for genetic neuromuscular disorders including not only SMA but also Duchenne muscular dystrophy, X-linked myotubular myopathy, myotonic dystrophy type 1, and Pompe disease. In their discussion of SMA, they consider gene expression modulation and gene therapy approaches. 

Read the review here. 

  • Gene therapy for neurological disorders: challenges and recent advancements.9

This review provides a summary of recent advances in targeted gene delivery for neurological diseases spanning the highly prevalent diseases to the rarer diseases like SMA. The authors also provide some insight into the future directions of gene therapy and the relevant challenges.

Read the review here. 

Managing SMA

Spinal muscular atrophy revisited.10

In this editorial, the author provides early clinical pictures of SMA and puts forth his long-standing belief that the disease need not be classified by age of onset but instead by the disease’s only known prognostic factor: respiratory compromise. The author also highlights new relevant research.

Read more here. 

Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment.11

In this article, data demonstrating that the levels of neurofilament light chain (NfL)– a marker of axonal degeneration –did not differ in the cerebrospinal fluid (CSF) of patients with SMA and healthy controls, nor did these levels differ in patients before and after nusinersen treatments. Only after a 4th injection of nusinersen was there a slight increase in CSF NfL in SMA patients. According to the authors of the study, NfL levels in the CSF does not provide a good marker for diagnosing or monitoring SMA in adolescents or adults with SMA type 2 or SMA type 3. 

Read more here. 

Understanding SMA

Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type 1 spinal muscular atrophy.1

This article describes a study of the nuclear reorganization of skeletal myofibers in a patient with SMA type 1. The results suggest that the primary effect of the deficiencies in the SMN protein that are observed in SMA patients occurs in the skeletal myofibers.

Read more here.

AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B-/SMA model mice.2

The authors of this article aimed to delve into how microRNA dysregulation may contribute to SMA pathology. They found that a specific microRNA – miR-23a – was downregulated in SMA motor neurons. When the researchers expressed miR-23a in a mouse model of SMA using an adeno-associated virus (AAV) vector, AAV9, SMA pathology was significantly reduced. Specifically, inducing miR-23a expression led to an enhancement in motor neuron size, a reduction in neuromuscular junction pathology, increased muscle fiber area, and longer survival.

Read more here.

References

1. Castillo-Iglesias MS, Berciano MT, Narcis JO, et al. Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type I spinal muscular atrophy. Histochem Cell Biol. June 2019. doi:10.1007/s00418-019-01792-6

2. Kaifer KA, Villalon E, O’Brien BS, et al. AAV9-Mediated Delivery of miR-23a Reduces Disease Severity in Smn2B-/SMA Model Mice. Hum Mol Genet. June 2019. doi:10.1093/hmg/ddz142

3. Torres-Benito L, Schneider S, Rombo R, et al. NCALD Antisense Oligonucleotide Therapy in Addition to Nusinersen further Ameliorates Spinal Muscular Atrophy in Mice. Am J Hum Genet. June 2019. doi:10.1016/j.ajhg.2019.05.008

4. Pane M, Coratti G, Sansone VA, et al. Nusinersen in type 1 Spinal Muscular Atrophy: 12-month real world data. Ann Neurol. June 2019. doi:10.1002/ana.25533

5. Frongia AL, Natera-de Benito D, Ortez C, et al. Salbutamol tolerability and efficacy in patients with spinal muscular atrophy type II. Neuromuscul Disord. April 2019. doi:10.1016/j.nmd.2019.04.003

6. Pattali R, Mou Y, Li X-J. AAV9 Vector: a Novel modality in gene therapy for spinal muscular atrophy. Gene Ther. June 2019. doi:10.1038/s41434-019-0085-4

7. Ravi B, Antonellis A, Sumner CJ, Lieberman AP. Genetic approaches to the treatment of inherited neuromuscular diseases. Hum Mol Genet. June 2019. doi:10.1093/hmg/ddz131

8. Ricci F, Vacchetti M, Brusa C, et al. New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges. Expert Rev Clin Pharmacol. June 2019. doi:10.1080/17512433.2019.1634543

9. Pena SA, Iyengar R, Eshraghi RS, et al. Gene Therapy for Neurological Disorders: Challenges and Recent Advancements. J Drug Target. June 2019:1-61. doi:10.1080/1061186X.2019.1630415

10. Dubowitz V. Spinal Muscular Atrophy Revisited. Neuromuscul Disord. 2019;29(6):413-414. doi:10.1016/j.nmd.2019.06.008

11. Wurster CD, Gunther R, Steinacker P, et al. Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment. Ther Adv Neurol Disord. 2019;12:1756286419846058. doi:10.1177/1756286419846058