Nusinersen in patients older than 7 months with spinal muscular atrophy type 1

ObjectiveTo evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1).MethodsPatients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32).ResultsWe treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene.ConclusionsOur results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease.ClinicalTrials.gov identifier:NCT02865109.Classification of evidenceThis study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

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

Advances in Therapy ◽

10.1007/s12325-019-00923-8 ◽

2019 ◽

Vol 36 (5) ◽

pp. 1164-1176 ◽

Cited By ~ 21

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

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Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I

Journal of Clinical Medicine ◽

10.3390/jcm10235540 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5540

Author(s):

Andrada Mirea ◽

Elena-Silvia Shelby ◽

Mihaela Axente ◽

Mihaela Badina ◽

Liliana Padure ◽

...

Keyword(s):

Combination Therapy ◽

Spinal Muscular Atrophy ◽

Motor Function ◽

Muscular Atrophy ◽

Combined Therapy ◽

Genetic Defect ◽

Survival Motor Neuron ◽

Control Group ◽

Type I ◽

Spinal Muscular Atrophy Type

Background: Spinal muscular atrophy (SMA) is a neuromuscular progressive disease, characterized by decreased amounts of survival motor neuron (SMN) protein, due to an autosomal recessive genetic defect. Despite recent research, there is still no cure. Nusinersen, an antisense oligonucleotide acting on the SMN2 gene, is intrathecally administered all life long, while onasemnogene abeparvovec-xioi, a gene therapy, is administered intravenously only once. Both therapies have proven efficacy, with best outcomes obtained when administered presymptomatically. In recent years, disease-modifying therapies such as nusinersen and onasemnogene abeparvovec-xioi have changed the natural history of SMA. Methods: We observed seven SMA type I patients, who received both therapies. We compared their motor function trajectories, ventilation hours and cough assist sessions to a control group of patients who received one therapy, in order to investigate whether combination therapy may be more effective than a single intervention alone. Results: Patients who received both therapies, compared to the monotherapy cohort, had the same motor function trajectory. Moreover, it was observed that the evolution of motor function was better in the 6 months following the first therapy than in the first 6 months after adding the second treatment. Conclusions: Our results suggest that early treatment is more important than combined therapy.

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Intellectual abilities, language comprehension, speech, and motor function in children with spinal muscular atrophy type 1

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09355-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Grazia Zappa ◽

Antonella LoMauro ◽

Giovanni Baranello ◽

Emilia Cavallo ◽

Priscilla Corti ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Function ◽

Language Comprehension ◽

Muscular Atrophy ◽

Neuromuscular Disorders ◽

Stable Condition ◽

Motor Dysfunction ◽

Speech Impairment ◽

Normal Range ◽

Spinal Muscular Atrophy Type

Abstract Background Spinal muscular atrophy (SMA) is a chronic, neuromuscular disease characterized by degeneration of spinal cord motor neurons, resulting in progressive muscular atrophy and weakness. SMA1 is the most severe form characterized by significant bulbar, respiratory, and motor dysfunction. SMA1 prevents children from speaking a clearly understandable and fluent language, with their communication being mainly characterized by eye movements, guttural sounds, and anarthria (type 1a); severe dysarthria (type 1b); and nasal voice and dyslalia (type 1c). The aim of this study was to analyze for the first time cognitive functions, language comprehension, and speech in natural history SMA1 children according to age and subtypes, to develop cognitive and language benchmarks that provide outcomes for the clinical medication trials that are changing SMA1 course/trajectory. Methods This is a retrospective study including 22 children with SMA1 (10 affected by subtype 1a-1b: AB and 12 by 1c: C) aged 3–11 years in clinical stable condition with a coded way to communicate “yes” and “no”. Data from the following assessments have been retrieved from patient charts: one-dimensional Raven test (RCPM), to evaluate cognitive development (IQ); ALS Severity Score (ALSSS) to evaluate speech disturbances; Brown Bellugy modified for Italian standards (TCGB) to evaluate language comprehension; and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) to assess motor functioning. Results SMA 1AB and 1C children were similar in age, with the former characterized by lower CHOP-INTEND scores compared to the latter. All 22 children had collaborated to RCPM and their median IQ was 120 with no difference (p = 0.945) between AB and C. Global median score of the speech domain of the ALSSS was 5; however, it was 2 in AB children, being significantly lower than C (6.5, p < 0.001). TCGB test had been completed by 13 children, with morphosyntactic comprehension being in the normal range (50). Although ALSSS did not correlate with both IQ and TCGB, it had a strong (p < 0.001) correlation with CHOP-INTEND described by an exponential rise to maximum. Conclusions Although speech and motor function were severely compromised, children with SMA1 showed general intelligence and language comprehension in the normal range. Speech impairment was strictly related to global motor impairment.

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Treatment with nusinersen in a girl with spinal muscular atrophy type 1 - Case report

Slovenian Medical Journal ◽

10.6016/zdravvestn.2902 ◽

2020 ◽

Vol 89 (5-6) ◽

pp. 320-326

Author(s):

Tanja Loboda ◽

Tita Butenko ◽

Tanja Golli ◽

Damjan Osredkar

Keyword(s):

Spinal Muscular Atrophy ◽

Respiratory Infections ◽

Muscular Atrophy ◽

Neuromuscular Disorders ◽

Neuromuscular Disorder ◽

Natural Course ◽

Dramatic Improvement ◽

Serious Adverse Events ◽

Spinal Muscular Atrophy Type

We report the case of a girl with spinal muscular atrophy (SMA) type 1, who is the first patient with SMA in Slovenia treated with nusinersen, the first disease modifying therapy available for these patients. SMA is an autosomal recessive neuromuscular disorder characterized by muscle weakness, atrophy and paralysis due to the degeneration of the anterior horn cells, leading to premature death, most commonly due to respiratory infections. Nusinersen, an antisense oligonucleotide, was clinically approved based on clinical trials showing dramatic improvement in the natural course of infantile-onset SMA. After the genetic confirmation of SMA, our girl was the first child in Slovenia to receive nusinersen, which was provided through an expanded access programme. She received intrathecal applications of nusinersen according to the protocol. No serious adverse events were observed. Assessment of her motor skills was performed using The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP – INTEND) before the beginning of treatment and after completing the first 7 applications of nusinersen. She scored 21/64 points before the introduction of treatment and 32/64 after the completion of treatment. In conclusion, nusinersen improved the CHOP – INTEND motor function score and has been effective in delaying the expected natural course of SMA in our patient.

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