Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

Mercuri, Eugenio; Finkel, Richard S.; Montes, Jacqueline; Mazzone, Elena; Sormani, Maria Pia; Main, Marion; Ramsey, Danielle; Mayhew, Anna; Glanzman, Allan M.; Dunaway, Sally; Salazar, Rachel; Pasternak, Amy; Quigley, Janet; Pane, Marika; Pera, Maria Carmela; Scoto, Mariacristina; Messina, Sonia; Sframeli, Maria; Vita, Gianluca; D’Amico, Adele; Hauwe, M. van den; Sivo, Serena; Goemans, Nathalie; Kaufmann, Petra; Darras, Basil T.; Bertini, Enrico; Muntoni, Francesco; Vivo, Darryl C. De

doi:10.1016/j.nmd.2015.10.006

Cited by 145 publications

(97 citation statements)

References 21 publications

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“…Patients with SMA type II have a better prognosis than those with type I disease, with 93% surviving to 25 years 6. After age 15, a relative stability in function develops with subsequent gradual decline over time 7. Age of onset is also a predictor of functional ability, with patients classified as SMA IIIa having a 73% probability of walking 10 years after diagnosis, whereas SMA type IIIb patients have a 97% probability of walking 10 years after diagnosis 8…”

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

“…The clinical heterogeneity in motor function is a challenge and connected with the range of possibilities for change in short time frames. The pattern of age‐related changes in motor function in SMA types II and III is nonlinear, and there are different patterns of progression between ambulant and nonambulant patients 7, 10. In nonambulant patients, variable improvement in motor function occurs up to 4 to 5 years of age, before functional ability (eg, in upper limbs) declines between 5 and 15 years.…”

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

“…In nonambulant patients, variable improvement in motor function occurs up to 4 to 5 years of age, before functional ability (eg, in upper limbs) declines between 5 and 15 years. After age 15, a relative stability in function develops with subsequent gradual decline over time 7. Decline in motor and respiratory function within a 12‐month period was often minor, although progression was variable between individuals 7, 9.…”

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

“…After age 15, a relative stability in function develops with subsequent gradual decline over time 7. Decline in motor and respiratory function within a 12‐month period was often minor, although progression was variable between individuals 7, 9. This slow rate of progression, particularly in milder phenotypes, poses a major challenge to clinical trials in SMA because most trials need to be completed within 1 to 2 years.…”

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

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Emerging therapies and challenges in spinal muscular atrophy

Farrar

Park

Vucic

et al. 2017

Annals of Neurology

173

170

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Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease‐modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease‐modifying therapies will necessitate monitoring programs to determine the long‐term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368

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Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

Section: Progress In Understanding the Natural History Of Smamentioning

confidence: 99%

See 2 more Smart Citations

Emerging therapies and challenges in spinal muscular atrophy

Farrar

Park

Vucic

et al. 2017

Annals of Neurology

173

170

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“…W przeciwieństwie do pacjentów z postacią ostrą, chorzy z formami przewlekłymi mogą nabywać nowe umiejętności ruchowe. U pacjentów niechodzących poprawa funkcjonalna następuje zwykle do 4-5 roku życia, w okresie między 5 i 15 rokiem życia obserwuje się często pogorszenie, po któ-rym następuje stabilizacja funkcji ruchowych [16]. Dla pacjentów chodzących najtrudniejszy wydaje się wiek dojrzewania (skoku wzrostowego), w którym wielu chorych traci zdolność samodzielnego chodzenia.…”

Section: Historia Naturalnaunclassified

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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Longitudinal characterization of biomarkers for spinal muscular atrophy

Bonati

Holiga

Hellbach

et al. 2017

Ann Clin Transl Neurol

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ObjectiveRecent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression.Methods18 SMA patients and 19 healthy volunteers (HV) were followed in this 52‐weeks observational study. Quantitative‐MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow‐up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow‐up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations.Results QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year.InterpretationWe probed a variety of quantitative measures for SMA in a slowly‐progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease‐modifying therapies.

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Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

Abstract: HighlightsThe paper reports for the first time patterns of progression in type 2 and 3 SMA.Different trajectories can be identified in ambulant and non-ambulant patients.Age appears to be an important factor in determining trajectories of progression.

Cited by 145 publications

References 21 publications

Emerging therapies and challenges in spinal muscular atrophy

Emerging therapies and challenges in spinal muscular atrophy

Spinal muscular atrophy – novel therapies, new challenges

Longitudinal characterization of biomarkers for spinal muscular atrophy

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