New Therapeutics Options for Pediatric Neuromuscular Disorders

Flotats‐Bastardas, Marina; Hahn, Andreas

doi:10.3389/fped.2020.583877

Cited by 11 publications

(13 citation statements)

References 94 publications

(103 reference statements)

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“…The DMD gene contains numerous hotspots for exon deletion. Among exon deletions in patients with DMD, approximately 20%, 13%, 12%, and 11% are amendable with the skipping of exons 51, 53, 45, and 44, respectively (16) . To treat a sufficient number of patients with DMD, several ASOs targeting the top three exons have been developed for clinical use by international researchers.…”

Section: Exon-skipping Therapy For Dmdmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Matsuo

2021

JMA J

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In 1995, we were the first to propose antisense oligonucleotide (ASO)-mediated exon-skipping therapy for the treatment of Duchenne muscular dystrophy (DMD), a noncurable, progressive muscle-wasting disease. DMD is caused by deletion mutations in one or more exons of the DMD gene that shift the translational reading frame and create a premature stop codon, thus prohibiting dystrophin production. The therapy aims to correct out-of-frame mRNAs to produce in-frame transcripts by removing an exon during splicing, with the resumption of dystrophin production. As this treatment is recognized as the most promising, many extensive studies have been performed to develop ASOs that induce the skipping of DMD exons. In 2016, an ASO designed to skip exon 51 was first approved by the Food and Drug Administration, which accelerated studies on the use of ASOs to treat other monogenic diseases. The ease of mRNA editing by ASO-mediated exon skipping has resulted in the further application of exon-skipping therapy to nonmonogenic diseases, such as diabetes mellites. Recently, this precision medicine strategy was drastically transformed for the emergent treatment of only one patient with one ASO, which represents a future aspect of ASO-mediated exon-skipping therapy for extremely rare diseases. Herein, the invention of ASO-mediated exon-skipping therapy for DMD and the current applications of ASO-mediated exon-skipping therapies are reviewed, and future perspectives on this therapeutic strategy are discussed. This overview will encourage studies on ASO-mediated exon-skipping therapy and will especially contribute to the development of treatments for noncurable diseases.

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Section: Exon-skipping Therapy For Dmdmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Matsuo

2021

JMA J

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“…Nusinersen nie przenika bariery krew-mózg dlatego podawany jest dokanałowo podczas nakłucia lędźwiowego. Początkowo podaje się 4 dawki wysycające (dzień 1, 14, 28, 63) a następnie kontynuacja polega na podawaniu jednej dawki co 3 miesiące [4,14,18]. Podczas terapii zalecane jest monitorowanie poziomu płytek krwi, układu krzepnięcia i kreatyniny [4].…”

Section: Rdzeniowy Zanik Mięsni (Sma)unclassified

“…Lekiem o podobnym mechanizmie działania do nusinersenu jest risdiplam (Evrysdi®), zarejestrowany do leczenia przez FDA w sierpniu 2020, w Europie oczekujący na rejestrację [4,18]. W Polsce dopuszczony tylko w ramach globalnego programu dostępu [4,18]. Risdiplam jest podawany codziennie w postaci syropu [4,14].…”

Section: Rdzeniowy Zanik Mięsni (Sma)unclassified

“…W maju 2019 roku w USA zarejestrowano pierwszą terapię genową do leczenia SMA pod nazwą onasemnogene abeparvovec-xioi (Zolgensma®) [4,18]. Leczenie polega na jednokrotnym, dożylnym podaniu preparatu zawierającego fragment DNA, uzupełniającego gen SMN, umożliwiającego powstanie stabilnego białka SMN.…”

Section: Rdzeniowy Zanik Mięsni (Sma)unclassified

“…Trwają również badania nad znalezieniem innej drogi podania leku, aby zmniejszyć dawkę i w ten sposób ograniczyć koszty [4,18]. Do lipca 2020 r. testowano podanie dokanałowe, jednak próby zostały wstrzymane z powodu obserwowanego zapalenia korzeni nerwowych w badaniach na zwierzętach [4,18] Terapie genowe i genetyczne zarejestrowane w leczeniu SMA podsumowano w tabeli I (tab. I).…”

Section: Rdzeniowy Zanik Mięsni (Sma)unclassified

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Terapie genowe i genetyczne w chorobach nerwowo- mięśniowych wieku dziecięcego

Jączak-Goździak¹,

Steinborn²

2020

Child Neurology

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Osiągnięcia genetyki, biologii molekularnej i inżynierii genetycznej zrewolucjonizowały współczesną medycynę: umożliwiły poznanie i zrozumienie genetycznego podłoża wielu chorób i utorowały drogę do poszukiwania leczenia poprzez naprawę wadliwych genów. W ostatnich latach największe sukcesy w zakresie terapii genowej i genetycznej zostały osiągnięte w chorobach nerwowo-mięśniowych wieku dziecięcego: w rdzeniowym zaniku mięśni i dystrofii mięśniowej Duchenne'a. To nowoczesne leczenie wykorzystuje różnorodne techniki takie jak: transport genów za pomocą wektorów wirusowych czy modyfikację ekspresji genów z użyciem antysensownych oligonukleotydów i "małych cząsteczek" oraz jeszcze badaną, ale bardzo obiecującą, edycję genomu z zastosowaniem systemu CRISPR-Cas9. W pracy przedstawiono przegląd: przełomowych terapii w leczeniu SMA i DMD oraz leczenia genetycznego, badanego w innych chorobach nerwowo- mięśniowych wieku dziecięcego

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Exogenous insulin‐like growth factor 1 attenuates cisplatin‐induced muscle atrophy in mice

Sakai

Asami

Naito

et al. 2021

J cachexia sarcopenia muscle

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Background A reduction in the skeletal muscle mass worsens the prognosis of patients with various cancers. Our previous studies indicated that cisplatin administration to mice caused muscle atrophy. This is a concern for human patients receiving cisplatin. The insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway stimulates the rate of protein synthesis in skeletal muscle. Thus, IGF-I can be a central therapeutic target for preventing the loss of skeletal muscle mass in muscle atrophy, although it remains unclear whether pharmacological activation of the IGF-1/PI3K/Akt pathway attenuates muscle atrophy induced by cisplatin. In this study, we examined whether exogenous recombinant human IGF-1 attenuated cisplatin-induced muscle atrophy. Methods Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for four consecutive days. On Day 5, quadriceps muscles were isolated. Mecasermin (recombinant human IGF-1) or the vehicle control was subcutaneously administered 30 min prior to cisplatin administration. A dietary restriction group achieving weight loss equivalent to that caused by cisplatin administration was used as a second control. C2C12 myotubes were treated with cisplatin with/without recombinant mouse IGF-1. The skeletal muscle protein synthesis/degradation pathway was analysed by histological and biochemical methods. Results Cisplatin reduced protein level of IGF-1 by about 85% compared with the vehicle group and also reduced IGF-1/PI3K/Akt signalling in skeletal muscle. Under this condition, the protein levels of muscle ring finger protein 1 (MuRF1) and atrophy gene 1 (atrogin-1) were increased in quadriceps muscles (MuRF1; 3.0 ± 0.1 folds, atrogin-1; 3.0 ± 0.3 folds, P < 0.001, respectively). The administration of a combination of cisplatin and IGF-1 significantly suppressed the cisplatin-induced downregulation of IGF-1/PI3K/Akt signalling and upregulation of MuRF1 and atrogin-1 (up to 1.6 ± 0.3 and 1.5 ± 0.4 folds, P < 0.001, respectively), resulting in diminished muscular atrophy. IGF-1 showed similar effects in cisplatin-treated C2C12 myotubes, as well as the quadriceps muscle in mice. Conclusions The downregulation of IGF-1 expression in skeletal muscle might be one of the factors playing an important role in the development of cisplatin-induced muscular atrophy. Compensating for this downregulation with exogenous IGF-1 suggests that it could be a therapeutic target for limiting the loss of skeletal muscle mass in cisplatin-induced muscle atrophy.

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New Therapeutics Options for Pediatric Neuromuscular Disorders

Cited by 11 publications

References 94 publications

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Terapie genowe i genetyczne w chorobach nerwowo- mięśniowych wieku dziecięcego

Exogenous insulin‐like growth factor 1 attenuates cisplatin‐induced muscle atrophy in mice

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