Spinal muscular atrophy is typically characterized as a motor neuron disease. Untreated patients with the most severe form, spinal muscular atrophy type 1, die early with infantile-onset progressive ...skeletal, bulbar, and respiratory muscle weakness. Such patients are now living longer due to new disease-modifying treatments such as gene replacement therapy (onasemnogene abeparvovec), recently approved by the US Food and Drug Administration, and nusinersen, a central nervous system-directed treatment which was approved by the US Food and Drug Administration three years ago. This has created an area of pressing clinical need: if spinal muscular atrophy is a multisystem disease, dysfunction of peripheral tissues and organs may become significant comorbidities as these patients survive into childhood and adulthood. In this review, we have compiled autopsy data, case reports, and cohort studies of peripheral tissue involvement in patients and animal models with spinal muscular atrophy. We have also evaluated preclinical studies addressing the question of whether peripheral expression of survival motor neuron is necessary and/or sufficient for motor neuron function and survival. Indeed, spinal muscular atrophy patient data suggest that spinal muscular atrophy is a multisystem disease with dysfunction in skeletal muscle, heart, kidney, liver, pancreas, spleen, bone, connective tissues, and immune systems. The peripheral requirement of SMN in each organ and how these contribute to motor neuron function and survival remains to be answered. A systemic (peripheral and central nervous system) approach to therapy during early development is most likely to effectively maximize positive clinical outcome.
Spinal muscular atrophies Darras, Basil T
The Pediatric clinics of North America,
06/2015, Letnik:
62, Številka:
3
Journal Article
Recenzirano
Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of ...the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Unlike other autosomal recessive diseases, the SMN gene has a unique structure (an inverted duplication) that presents potential therapeutic targets. Although there is currently no effective treatment of SMA, the field of translational research in this disorder is active and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with SMA also offer hope for improved life expectancy and quality of life.
Risdiplam in Type 1 Spinal Muscular Atrophy Baranello, Giovanni; Darras, Basil T; Day, John W ...
The New England journal of medicine,
03/2021, Letnik:
384, Številka:
10
Journal Article, Web Resource
Recenzirano
Odprti dostop
The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status ...were reported.
OBJECTIVES:Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).
METHODS:Patients were enrolled at 3 study sites and followed for up to ...36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.
RESULTS:Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Childrenʼs Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02).
CONCLUSIONS:Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.
We investigated the presence of non-neuromuscular phenotypes in patients affected by Spinal Muscular Atrophy (SMA), a disorder caused by a mutation in the Survival of Motor Neuron (SMN) gene, and ...whether these phenotypes may be clinically detectable prior to clinical signs of neuromuscular degeneration and therefore independent of muscle weakness.
We utilized a de-identified database of insurance claims to explore the health of 1,038 SMA patients compared to controls. Two analyses were performed: (1) claims from the entire insurance coverage window; and (2) for SMA patients, claims prior to diagnosis of any neuromuscular disease or evidence of major neuromuscular degeneration to increase the chance that phenotypes could be attributed directly to reduced SMN levels. Logistic regression was used to determine whether phenotypes were diagnosed at significantly different rates between SMA patients and controls and to obtain covariate-adjusted odds ratios.
Results from the entire coverage window revealed a broad spectrum of phenotypes that are differentially diagnosed in SMA subjects compared to controls. Moreover, data from SMA patients prior to their first clinical signs of neuromuscular degeneration revealed numerous non-neuromuscular phenotypes including defects within the cardiovascular, gastrointestinal, metabolic, reproductive, and skeletal systems. Furthermore, our data provide evidence of a potential ordering of disease progression beginning with these non-neuromuscular phenotypes.
Our data point to a direct relationship between early, detectable non-neuromuscular symptoms and SMN deficiency. Our findings are particularly important for evaluating the efficacy of SMN-increasing therapies for SMA, comparing the effectiveness of local versus systemically delivered therapeutics, and determining the optimal therapeutic treatment window prior to irreversible neuromuscular damage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The pre-mRNA
SMN2
splicing modifier risdiplam was administered orally to 41 infants with type 1 spinal muscular atrophy. After 12 months of treatment, 12 infants were able to sit without support, and ...most had better scores on motor-performance scales than the upper limit of confidence intervals from historical controls.
OBJECTIVE:To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter ...splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA).
METHODS:Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.
RESULTS:A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9–14 months postdose (5.8 points; p = 0.008) during the extension study.
CONCLUSIONS:Results from this study support continued development of nusinersen for treatment of SMA.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
ABSTRACT
Introduction
There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the ...extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.
Methods
An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.
Results
Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.
Conclusions
The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi‐center clinical research. Muscle Nerve 55: 869–874, 2017
Spinal muscular atrophy was the most common inherited cause of infant death until 2016, when three therapies became available: the antisense oligonucleotide nusinersen, gene replacement therapy with ...onasemnogene abeparvovec, and the small-molecule splicing modifier risdiplam. These drugs compensate for deficient survival motor neuron protein and have improved lifespan and quality of life in infants and children with spinal muscular atrophy. Given the lifelong implications of these innovative therapies, ways to detect and manage treatment-modified disease characteristics are needed. All three drugs are more effective when given before development of symptoms, or as early as possible in individuals who have already developed symptoms. Early subtle symptoms might be missed, and disease onset might occur in utero in severe spinal muscular atrophy subtypes; in some countries, newborn screening is allowing diagnosis soon after birth and early treatment. Adults with spinal muscular atrophy report stabilisation of disease and less fatigue with treatment. These subjective benefits need to be weighed against the high costs of the drugs to patients and health-care systems. Clinical consensus is required on therapeutic windows and on outcome measures and biomarkers that can be used to monitor drug benefit, toxicity, and treatment-modified disease characteristics.
The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I ...however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).
Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores.
A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.
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