scholarly journals P.064 FIREFISH Part 1: 1-year results on motor function in infants with Type 1 spinal muscular atrophy (SMA) receiving risdiplam (RG7916)

2019 ◽  
Vol 46 (s1) ◽  
pp. S31 ◽  
Author(s):  
TJ Seabrook ◽  
G Baranello ◽  
L Servais ◽  
JW Day ◽  
N Deconinck ◽  
...  
Keyword(s):  
Motor Function ◽  
Muscular Atrophy ◽  
Protein A ◽  
Analysis Data ◽  
Open Label ◽  
Protein Levels ◽  
Gene Copies ◽  
Patient Withdrawal ◽  
Smn Protein

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.

Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3

2021 ◽  
pp. 1-6
Author(s):  
Miriam Hiebeler ◽  
Angela Abicht ◽  
Peter Reilich ◽  
Maggie C. Walter
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Rna Splicing ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Spinal Muscular Atrophy Type ◽  
Protein Levels ◽  
Discontinuation Of Treatment ◽  
Smn Protein ◽  
Treatment Onset

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disease leading to ongoing degeneration of anterior horn cells in the spinal cord. Nusinersen is the first approved treatment for the condition, an intrathecally administered antisense oligonucleotide. It modulates pre-RNA splicing of the SMN2 gene and increases full-length SMN protein expression, thereby increasing SMN protein levels. The benefit of Nusinersen for patients with spinal muscular atrophy type 3 (SMA3) has recently been shown in several real-world cohorts. Objective: We aim to elucidate not only the effect of therapy with Nusinersen, but the development of the disease course after discontinuation of treatment. To our knowledge, there are so far no reports on the effects of Nusinersen discontinuation. Methods: We report on a 45-year-old female patient with genetically confirmed SMA3 and a disease duration of 40 years prior to treatment onset. Results: The patient was non-ambulantory, best motor function at treatment onset was holding arms with support, reflected in MRC of 3/5 in upper limbs. After having received Nusinersen for 11 months without complications, the patient showed improvement in motor functions, as measured by hand grip measurement (HGS), Hammersmith Functional Rating Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Due to worsening of a pre-existing anxiety disorder, treatment was discontinued after six injections. Sixteen months later, progression of the disease became evident with worsening of HFMSE and RULM scores, while hand strength remained stable. Conclusion: Treatment with Nusinersen in SMA3 improves motor function in longstanding disease even in clinically advanced stages; however, after discontinuation of treatment, further progression mirroring the natural history of the disease is anticipated.

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Science ◽  
2014 ◽  
Vol 345 (6197) ◽  
pp. 688-693 ◽  
Author(s):  
Nikolai A. Naryshkin ◽  
Marla Weetall ◽  
Amal Dakka ◽  
Jana Narasimhan ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Messenger Rna ◽  
High Selectivity ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Chemical Screening ◽  
Protein Levels ◽  
Smn Protein ◽  
Survival Of Motor Neuron

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

scholarly journals P.063 SUNFISH Part 1 results and Part 2 trial design in patients with type 2/3 spinal muscular atrophy (SMA) receiving risdiplam (RG7916)

2019 ◽  
Vol 46 (s1) ◽  
pp. S31
Author(s):  
C Campbell ◽  
E Mercuri ◽  
G Baranello ◽  
J Kirschner ◽  
L Servais ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Protein A ◽  
Fold Increase ◽  
Underlying Disease ◽  
Double Blind ◽  
Protein Levels ◽  
Smn Protein ◽  
Survival Of Motor Neuron ◽  
Dose Levels

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Maximilian Paul Thelen ◽  
Brunhilde Wirth ◽  
Min Jeong Kye
Keyword(s):  
Protein Synthesis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Complex I ◽  
Energy Homeostasis ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Translational Initiation ◽  
Protein Levels ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients.

scholarly journals Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1

2019 ◽  
Vol 36 (5) ◽  
pp. 1164-1176 ◽  
Author(s):  
Omar Dabbous ◽  
Benit Maru ◽  
Jeroen P. Jansen ◽  
Maria Lorenzi ◽  
Martin Cloutier ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Muscular Atrophy ◽  
Spinal Muscular Atrophy Type

scholarly journals Nusinersen in later-onset spinal muscular atrophy

Neurology ◽  
2019 ◽  
Vol 92 (21) ◽  
pp. e2492-e2506 ◽  
Author(s):  
Basil T. Darras ◽  
Claudia A. Chiriboga ◽  
Susan T. Iannaccone ◽  
Kathryn J. Swoboda ◽  
Jacqueline Montes ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Extension Study ◽  
Type Ii ◽  
Open Label ◽  
Type Iii ◽  
Link Type ◽  
Phase 1B

ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.ResultsTwenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.ConclusionsNusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.Clinicaltrials.gov identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

scholarly journals Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy

2018 ◽  
Vol 27 (16) ◽  
pp. 2851-2862 ◽  
Author(s):  
Ewout J N Groen ◽  
Elena Perenthaler ◽  
Natalie L Courtney ◽  
Crispin Y Jordan ◽  
Hannah K Shorrock ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Tissue Specific ◽  
Protein Levels ◽  
Smn Protein
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