Observational study of spinal muscular atrophy type I and implications for clinical trials

Finkel, Richard S.; McDermott, Michael P.; Kaufmann, Petra; Darras, Basil T.; Chung, Wendy K.; Sproule, Douglas M.; Kang, Peter B.; Foley, A. Reghan; Yang, Michelle; Martens, William; Oskoui, Maryam; Glanzman, Allan M.; Flickinger, Jean; Montes, Jacqueline; Dunaway, Sally; O’Hagen, Jessica; Quigley, Janet; Riley, Susan; Benton, Maryjane; Ryan, Patricia; Montgomery, Megan; Marra, Jonathan; Gooch, Clifton L.; Vivo, Darryl C. De

doi:10.1212/wnl.0000000000000741

Cited by 376 publications

(371 citation statements)

References 21 publications

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“…This finding, while not surprising, is remarkably consistent with prior studies 19, 33. This consistency, obtained in a multicenter format similar to what would be expected in a large clinical trial context, is an important replication and validation of earlier single center studies (Finkel, Krosschell, and Swoboda, unpublished data).…”

Section: Discussionsupporting

confidence: 90%

“…After testing, all subjects were required to have a 20‐minute rest period that could include nursing/feeding. Subjects who scored less than 41 on the TIMSPI were then evaluated using The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP‐INTEND) which is a validated 16‐item, 64‐point scale shown to be reliable in SMA type 1 subjects 19, 24. Subjects scoring 41 or greater on the TIMPSI were evaluated using the Alberta Infant Motor Scale (AIMS), a 58‐item observational scale developed to assess motor development in children from birth until independent walking 25, 26…”

Section: Methodsmentioning

confidence: 99%

“…With the advent of standardized care guidelines,17 the mortality of SMA type 1 infants has been reduced at 2 years of age to 30%, with nearly half of these infants dependent upon noninvasive ventilation 18. In a recent observational study, SMA infants who developed symptoms prior to 6 months of age demonstrated very poor motor function and significant motor loss electrophysiologically at the enrollment visit 19. Thus, there is heightened need to identify and validate physiological and molecular biomarkers in the SMA type 1 population and to obtain longitudinal outcome measures for use in future SMA infant clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Kolb

Coffey

Yankey

et al. 2016

Ann Clin Transl Neurol

106

119

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ObjectiveThis study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).MethodsThis prospective, multi‐center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits.ResultsEnrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high‐frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts.InterpretationBy the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Kolb

Coffey

Yankey

et al. 2016

Ann Clin Transl Neurol

106

119

View full text Add to dashboard Cite

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“…Wśród dzieci z SMA1 liczba kopii genu SMN2 stanowi silny biomarkerkrzywa przeżycia jest krótsza u chorych z 2 kopiami SMN2. Mediana wieku przeżycia lub wieku wprowadzenia sztucznej wentylacji (>16 godzin na dobę) wynosi 13,5 miesią-ca [10]. Okres ten skraca się do 10,5 miesiąca dla dzieci z 2 kopiami SMN2.…”

Section: Historia Naturalnaunclassified

“…Aktualnie zarejestrowano w SMA 98 badań, w tym badania historii naturalnej. Badania historii naturalnej polegające na ocenie przebiegu choroby przy pomocy walidowanych skal w predefiniowanych odstępach czasu są niezwykle ważne, ponieważ pomagają w projektowaniu przyszłych badań klinicznych leków, któ-re przebieg choroby znacząco złagodzić [10,13,16].…”

Section: Próby Terapeutyczneunclassified

Spinal muscular atrophy – novel therapies, new challenges

Jędrzejowska¹,

Kostera‐Pruszczyk²

2017

Child Neurology

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STRESZCZENIERdzeniowy zanik mięśni jest postępującą chorobą neurodegeneracyjną, w przebiegu której dochodzi do utraty motoneuronów rdzenia kręgowego, a w konsekwencji osłabienia i zaniku mięśni. Choroba charakteryzuje się bardzo dużą zmiennością przebiegu klinicznego -od letalnej formy wrodzonej po postać dorosłą, o średniej przeżycia jak w populacji ogólnej. Choroba związana jest z mutacjami genu SMN1. Liczba kopii bliźniaczo podobnego genu SMN2 warunkuje nasilenie objawów klinicznych. Analizy ostatnich lat zaowocowały weryfikacją aktualnej klasyfikacji, poprawą standardów opieki, poznaniem przebiegu historii naturalnej choroby. W zderzeniu z nowymi badaniami nad podłożem molekularnym i patogenezą choroby możliwe stało się podjęcie prób terapeutycznych. Badania kliniczne wykazały skuteczność nusinersenu (anysensowny oligonukleotyd), i doprowadziły do rejestracji leku do leczenia SMA. Najlepsze efekty uzyskano u pacjentów, u których włączono leczenie w okresie przedobjawowym. Trwają badania nad kolejnymi substancjami, których działanie oparte jest o różnorodne strategie-począwszy od terapii genowej (AVXS101), przez mikromolekuły modyfikujące składanie pre-mRNA SMN2 (LMI070, RG7916), po neuroprotektory (Olesoxime) i wiele innych. W pracy dokonujemy przeglądu najnowszych danych dotyczą-cych klasyfikacji, historii naturalnej, standardów opieki i prób terapeutycznych. Wczesne rozpoznanie i leczenie może zmienić historię naturalną choroby. Dlatego tak ważne wydaje się wczesne rozpoznanie, a w przyszłości być może wprowadzenie skriningu noworodkowego. Słowa kluczowe: SMA 5q, białko SMN, terapia. ABSTRACTSpinal muscle atrophy (SMA) is a progressive neurodegenerative disease that results in the loss of motoneurons in the spinal cord and, consequently, in muscle weakness and atrophy. The disease is characterized by high variability of the clinical course -from the early neonatal form to the adult form, with the average survival as in the general population. The disease is caused by mutations in the SMN1 gene. The number of copies of a similar SMN2 gene determines the severity of clinical symptoms. Recent analyzes allowed to verify current classification, improve care standards, learn the natural history of SMA. Clinical studies showed the efficacy of nusinersen (an antysense oligonucleotide) and led to the registration of the drug for SMA treatment. The best results were seen in presymptomatic patients. Research is underway on substances that are based on a variety of strategies, from gene therapy (AVXS101) to SMN2 pre-mRNA modulation micronucleus (LMI070, RG7916) to neuroprotectants (Olesoxime) and many others. We review the latest data on classification, natural history, care standards and therapeutic trials. Early diagnosis and treatment can change the natural history of the disease. That is why it is so important to have an early diagnosis and, perhaps, a neonatal screening in the future.

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Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

et al. 2021

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IMPORTANCE This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.OBJECTIVE The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. DESIGN, SETTING, AND PARTICIPANTSThis study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017 at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 10 13 vg/kg; or therapeutic dose, 1.1 × 10 14 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.EXPOSURES Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. MAIN OUTCOMES AND MEASURESThe primary outcome measure was the incidence of serious adverse events (SAEs).RESULTS At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. CONCLUSIONS AND RELEVANCEThe findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03421977.

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Observational study of spinal muscular atrophy type I and implications for clinical trials

Cited by 376 publications

References 21 publications

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

Spinal muscular atrophy – novel therapies, new challenges

Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

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