209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

doi:10.1016/j.nmd.2015.04.009

Neuromuscular Disorders

Volume 25, Issue 7, July 2015, Pages 593-602

https://doi.org/10.1016/j.nmd.2015.04.009 Get rights and content

Highlights

•
An updated classification for SMA is presented.
•
The utility and limitations of animal models in SMA is discussed.
•
Biomarkers that are potentially useful in a clinical trial setting are reviewed.
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A detailed review of clinical outcome measures for use in a clinical trial is tabulated.

Introduction

Twenty-four researchers and industry representatives from 9 different countries (USA, Spain, Italy, France, Germany, Switzerland, Sweden, The Netherlands, United Kingdom), one patient and representatives of SMA Europe and from the SMA Foundation met in Holland on the weekend of the 7th–9th of November 2014 to update current knowledge on clinical trials and outcome measures for spinal muscular atrophy (SMA).

Section snippets

Background

Spinal muscular atrophy (SMA) is one of the most common neuromuscular diseases. While SMA is a monogenic disorder, there is a broad range of phenotypes from very weak infants unable to sit (type 1), non-ambulant children able to sit (type 2), to ambulant children (type 3). Further subtypes have also been suggested at the 2 ends of the clinical severity: SMA type 0, in which onset is in utero with reduced or absent movements, contractures, and requirement for mechanical ventilation support at

Molecular genetic topics in SMA

The genetic basis of SMA is well established [2]. Deletions or other mutations in the SMN1 gene cause SMA. An almost identical gene, SMN2, closely located on the same chromosome, is invariably present, as complete ablation of both SMN1 and SMN2 is considered to be lethal. Diagnostic testing for genetic confirmation of the diagnosis is now readily available in commercial and clinical labs around the world. The number of copies of the SMN2 gene is inversely related to severity but in individual

Conclusions

The workshop ended on Sunday morning with a discussion on future collaborative strategies. These ranged from the distribution of samples with known number of copy number to participating laboratories for quality control; to the work towards improved information that could help the regulatory authorities to better understand the content and concept behind the various functional scales; and to ensure there is a central repository of all scales used, under the TREAT-NMD domain (//www.treat-nmd.eu/resources/outcome-measures/registry-of-outcome-measures/

Participants – ENMC SMA Workshop Study Group*

Enrico Bertini, Rome, Italy
Alexandra Breukel, ENMC
Arthur Burghes, Columbus (Ohio), USA
Karen Chen, New York, USA
Richard Finkel, Orlando, USA
Mencia de Lemus, Madrid, Spain
Jean-Yves Hogrel, Paris, France
Omar Khwaja, Basil, Switzerland
Jan Kirschner, Freiburg, Germany
Marion Main, London, UK
Elena Mazzone, Rome, Italy
Eugenio Mercuri, Rome, Italy
Jacqueline Montes, New York, USA
Francesco Muntoni, London, UK
Danielle Ramsey, London, UK
Thomas Sejersen, Stockholm, Sweden
Charlotte Summer, Baltimore, USA

Acknowledgements

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors:

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Association Française contre les Myopathies (France)
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Deutsche Gesellschaft für Muskelkranke (Germany)
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Muscular Dystrophy Campaign (UK)
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Muskelsvindfonden (Denmark)
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Prinses Beatrix Spierfonds (The Netherlands)
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Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)
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Telethon Foundation (Italy)
-
Spierziekten Nederland (The Netherlands)

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Cited by (162)

Effect of nusinersen after 3 years of treatment in 57 young children with SMA in terms of SMN2 copy number or type
2024, Archives de Pediatrie
Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number.
We found that 93% of the patients gained new motor skills during the 3 years—standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies.
Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies.
Sleep architecture and Nusinersen therapy in children with Spinal Muscular Atrophy type 1
2023, Sleep Medicine
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder, the phenotype of the disease is caused by the mutation of the SMN1 (survival motor neuron 1) gene which encodes for the SMN protein. Innovative treatments for SMA have become available and the first molecule approved is Nusinersen, an antisense oligonucleotide that increases the production of SMN protein. Nusinersen has been shown to be associated with a significant motor improvement and an increase of the event‐free survival. For these reasons the aim of the present study is to assess if Nusinersen is able modify sleep architecture and microstructure and to improve sleep structure in these patients.
Sixteen patients affected by SMA1 were enrolled in the study (4 boys, 12 girls; median age 72.5 months, intelligence quotient range 24–84). All patients underwent complete nocturnal PSG before the start of the treatment trough intrathecal injections with Nusinersen (T0) and after the fifth infusion (day 180, T180). PSG recordings were visually scored and interpreted according to the indications of the American Academy of Sleep Medicine (AASM) and and microstructure by means of the Cyclic Alternating Pattern (CAP).
After 6 months therapy we found a significantly reduced sleep latency and a significantly increased sleep efficiency. Regarding sleep microstructure parameters (CAP), we did not find any significant change after therapy however, it is worth mentioning that a moderate effect size was observed for the increase in CAP A3 index.
We observed short-term effects of Nusinersen on sleep with an improvement in sleep efficiency and reduction in sleep onset latency; regarding sleep microstructure, a moderate effect size was found for the number of CAP A3 subtypes that slightly increased, possibly indicating a slightly higher arousability. This finding points at a probably overall better sleep pattern organization associated with the treatment, but they need to be confirmed by larger studies with patients treated earlier in life and for a longer period.
Challenges and future perspective of antisense therapy for spinal muscular atrophy: A review
2023, European Journal of Cell Biology
Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the death of motor neurons and progressive muscle weakness. SMN1 normally produces an essential protein called SMN. Although humans possess a paralogous gene called SMN2, ∼90% of the SMN it produces is non-functional. This is due to a mutation in SMN2 that causes the skipping of a required exon during splicing of the pre-mRNA. The first treatment for SMA, nusinersen (brand name Spinraza), was approved by the FDA in 2016 and by the EMU in 2017. Nusinersen is an antisense oligonucleotide-based therapy that alters the splicing of SMN2 to make functional full-length SMN protein. Despite the recent advancements in antisense oligonucleotide therapy and SMA treatment development, nusinersen is faced with a multitude of challenges, such as intracellular and systemic delivery. In recent years, the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) in antisense therapy has gained interest. These are antisense oligonucleotides conjugated to cell-penetrating peptides such as Pips and DG9, and they have the potential to address the challenges associated with delivery. This review focuses on the historic milestones, development, current challenges, and future perspectives of antisense therapy for SMA.
Muscle impairment in MRI affect variability in treatment response to nusinersen in patients with spinal muscular atrophy type 2 and 3: A retrospective cohort study
2023, Brain and Development
Real-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response.
We retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treatment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline.
Of these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function.
The degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change.
A study on the incidence and prevalence of 5q spinal muscular atrophy in Canada using multiple data sources
2024, Canadian Journal of Neurological Sciences
Design and Validation of a Clinical Outcome Measure for Adolescents and Adult Patients with Spinal Muscular Atrophy: SMA Life Study Protocol
2024, Neurology and Therapy

View all citing articles on Scopus

¹: Listed at the end of this report.

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Workshop report209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

Highlights

Introduction

Section snippets

Background

Molecular genetic topics in SMA

Conclusions

Participants – ENMC SMA Workshop Study Group*

Acknowledgements

First page preview

Neuromuscul Disord

Solving the puzzle of spinal muscular atrophy: what are the missing pieces?

Am J Med Genet A

A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy

Hum Mutat

A positive modifier of spinal muscular atrophy in the SMN2 gene

Am J Hum Genet

How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches

Curr Opin Genet Dev

Abnormal motor phenotype in the SMNDelta7 mouse model of spinal muscular atrophy

Neurobiol Dis

A mouse model for spinal muscular atrophy

Nat Genet

Molecular and phenotypic reassessment of an infrequently used mouse model for spinal muscular atrophy

Biochem Biophys Res Commun

Electrophysiological biomarkers in spinal muscular atrophy: preclinical proof of concept

Ann Clin Transl Neurol

A large animal model of spinal muscular atrophy and correction of phenotype

Ann Neurol

Density, calibre and ramification of muscle capillaries are altered in a mouse model of severe spinal muscular atrophy

Neuromuscul Disord

Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics

Hum Mol Genet

Abnormalities in early markers of muscle involvement support a delay in myogenesis in spinal muscular atrophy

J Neuropathol Exp Neurol

Spectrum of neuropathophysiology in spinal muscular atrophy type I

J Neuropathol Exp Neurol

Synaptic defects in type I spinal muscular atrophy in human development

J Pathol

SMA-MAP: a plasma protein panel for spinal muscular atrophy

PLoS ONE

The motor neuron response to SMN1 deficiency in spinal muscular atrophy

Muscle Nerve

Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3

Neurology

The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation

Eur J Paediatr Neurol

Reliability of the Hammersmith functional motor scale for spinal muscular atrophy in a multicentric study

Neuromuscul Disord

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

Neuromuscul Disord

Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy

Muscle Nerve

An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients

Neuromuscul Disord

Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III

J Child Neurol

Reliability and validity of outcome measures of in-hospital and at-home visits in a randomized, double-blind, placebo-controlled trial for spinal muscular atrophy

J Child Neurol

A motor function measure for neuromuscular diseases. Construction and validation study

Neuromuscul Disord

Motor function measure: validation of a short form for young children with neuromuscular diseases

Arch Phys Med Rehabil

Assessing upper limb function in nonambulant SMA patients: development of a new module

Neuromuscul Disord

The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability

Neuromuscul Disord

Reliability and validity of the TIMPSI for infants with spinal muscular atrophy type I

Pediatr Phys Ther

Compound muscle action potential and motor function in children with spinal muscular atrophy

Muscle Nerve

Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy

Neurology

Workshop report
209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands