<i>SMN2</i>
            splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Naryshkin, Nikolai; Weetall, Marla; Dakka, Amal; Narasimhan, Jana; Zhao, Xin; Feng, Zhichun; Ling, Karen; Karp, Gary M.; Qi, Hongyan; Woll, Matthew G.; Chen, Guangming; Zhang, Nanjing; Gabbeta, Vijayalakshmi; Vazirani, Priya; Bhattacharyya, Arkaprava; Furia, Bansri; Risher, Nicole; Sheedy, Josephine; Kong, Ronald; Ma, Jiyuan; Turpoff, Anthony; Lee, Chang-Sun; Zhang, Xiaoyan; Moon, Young-Choon; Trifillis, Panayiota; Welch, Ellen; Colacino, Joseph M.; Babiak, John; Almstead, Neil G.; Peltz, Stuart W.; Eng, Loren A.; Chen, Karen S.; Mull, Jesse L.; Lynes, Maureen S.; Rubin, Lee L.; Fontoura, Paulo; Santarelli, Luca; Haehnke, Daniel; McCarthy, Kathleen; Schmucki, Roland; Ebeling, Martin; Sivaramakrishnan, Manaswini; Ko, Chien‐Ping; Paushkin, Sergey; Ratni, Hasane; Gerlach, Irene; Ghosh, Anirvan; Metzger, Friedrich

doi:10.1126/science.1250127

Cited by 462 publications

(454 citation statements)

References 57 publications

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“…Efficacy testing of SMA therapies has been primarily restricted to mouse models with very low levels of SMN, such as the Δ7 mouse, and is referred to as one of the "severe models," with a median survival of 12-14 d after birth (6)(7)(8)(9)(10)(11)(12). Attempts to generate a robust intermediate model have resulted in mice with near-normal life spans and little to no neuromuscular phenotype (13,14).…”

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confidence: 99%

“…Among these is the narrow window for testing therapeutic interventions, as the short overall survival time of these mice limits the study of postonset interventions (11,(15)(16)(17). In these severe SMA mice, several studies have demonstrated that successful intervention in the disease course is limited to the early postnatal days (PNDs) (10,17,18). Whether this observation holds true in milder models of SMA remains to be answered but is a critical question, as type II/III patients represent the majority currently awaiting treatment.…”

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confidence: 99%

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Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.

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mentioning

confidence: 99%

mentioning

confidence: 99%

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Badania podstawowe wykazały selektywny wpływ cząsteczek na zwiększenie syntezy białka SMN w hodowli komórkowej. W modelu mysim SMA czą-steczki te wykazały dobrą biodostępność, a przede wszystkim pozytywny wpływ na przeżycie i funkcję ruchową zwierząt [40]. Aktualnie trwa rekrutacja do trzech badań klinicznych cząsteczki RG7916, w tym badania fazy 2 Firefish (ClinicalTrials.gov Identifier: NCT02913482) i Sunfish (NCT02908685) oceniające skuteczność i bezpieczeństwo odpowiednio u pacjentów z SMA1 i MSA2-3.…”

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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“…Interestingly, a recent paper reports novel smSMs developed for survival motor neuron splicing and treatment of spinal muscular atrophy. 68 The compounds resulted from a screen using a splicing reporter that followed the endogenous splicing event. RNAseq was performed to inquire specificity.…”

Section: Manipulation Of As As a Potential Therapeutic Avenue In Ckdmentioning

confidence: 99%

Alternative Splicing in CKD

Stevens

Oltean

2016

JASN

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Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with $94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.

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

Cited by 462 publications

References 57 publications

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Spinal muscular atrophy – novel therapies, new challenges

Alternative Splicing in CKD

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