Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model

Nizzardo, Monica; Simone, Carla; Rizzo, Federica; Salani, Sabrina; Dametti, Sara; Rinchetti, Paola; Bo, Roberto Del; Foust, Kevin D.; Kaspar, Brian K.; Bresolin, Nereo; Comi, Giacomo Pietro; Corti, Stefania

doi:10.1126/sciadv.1500078

Cited by 43 publications

(47 citation statements)

References 26 publications

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“…Previous reports have shown that AAV9 vectors allow for a long‐term expression of the genes that they carry (Bernardes de Jesus et al ., ; Nizzardo et al ., ). To address whether AAV9‐TRF1 treatment allowed for long‐term TRF1 expression, we compared TRF1 mRNA and protein levels at the humane end point in our 2‐year‐old mouse cohort in which all mice had been already sacrificed.…”

Section: Resultsmentioning

confidence: 97%

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

et al. 2017

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SummaryThe shelterin complex protects telomeres by preventing them from being degraded and recognized as double‐strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1‐year‐old) and old (2‐year‐old) mice using gene therapy can delay age‐associated pathologies. To this end, we used the nonintegrative adeno‐associated serotype 9 vector (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9‐TRF1 gene therapy significantly prevented age‐related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9‐TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere‐associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9‐TRF1 gene therapy results in an improved mouse health span.

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Section: Resultsmentioning

confidence: 97%

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

et al. 2017

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“…The benefits obtained by the in vitro use of neurotrophic factors and pharmacological agents are not encouraging, 38,39 but better results have been obtained with the injection of rAAV in nmd mice. 32,48 The pathogenetic mechanisms underlying this disease are complex and not yet completely deciphered; in fact, mutations in the same IGHMBP2 gene can determine very serious (SMARD1) or mild phenotypes (CMT). Moreover, SMARD1 itself demonstrated substantial variability in terms of age of presentation, severity of the symptoms and survival.…”

Section: Discussionmentioning

confidence: 99%

“…The factors Oct3/4, Sox2, c-Myc and Klf4 act together to overwhelm skin gene expression in fibroblasts and can activate genes encoding hESC proteins, thus inducing the reprogramming of somatic cells into iPSCs 28. Our group provided one of the first descriptions of the generation of IGHMBP2-mutated iPSCs from SMARD1 patients for in vitro studies of SMARD1 31,32. Our group provided one of the first descriptions of the generation of IGHMBP2-mutated iPSCs from SMARD1 patients for in vitro studies of SMARD1 31,32.…”

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confidence: 99%

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Saladini

Nizzardo

Govoni

et al. 2019

J Cellular Molecular Medi

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.

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“…Wirusy AAV wykorzystano w badaniach przedklinicznych m.in. w próbach leczenia przeponowej postaci rdzeniowego zaniku mięśni (SMARD1) [112]. Jak wspomniano wyżej, choroba spowodowana jest mutacjami w genie IGHMBP2 i dziedziczona w sposób autosomalny recesywny, podobnie jak CMT2S spowodowane mutacjami w tym samych genie [57].…”

Section: Próby Terapii Genowej W Cmtunclassified

“…Usprawnieniu uległy połączenia nerwowo-mięśniowe, a także wzrosła wielkość włókien mięśniowych. W hodowlach komórkowych uwidoczniono wyraźne zmniejszenie ubytku aksonów oraz ich wydłużenie [112]. Prowadzone badania u chorych ze SMARD1, stanowią również szansę na skuteczną terapię w przypadku chorych z CMT2S.…”

Section: Próby Terapii Genowej W Cmtunclassified

Perspektywy terapii w polineuropatiach genetycznie uwarunkowanych

Kochański¹,

Kabzińska²,

Rzepnikowska³

et al. 2018

Postepy Biochem

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Polineuropatie genetycznie uwarunkowane (HMSN, ang. hereditary motor and sensory neuropathies) zwane również chorobami kręgu Charcot-Marie-Tooth (CMT) stanowią niezwykle heterogenną genetycznie (ponad 80 genów) grupę chorób obwodowego układu nerwowego człowieka. Istotą chorób kręgu CMT jest powolnie postępujący zanik mięśni dystalnych kończyn dolnych (podudzia) i górnych (przedramiona). Jak dotąd nie opracowano skutecznej metody leczenia CMT. W pracy przedstawiono obecny stan wiedzy dotyczący kliniki, patogenezy molekularnej i pierwszych prób terapeutycznych w CMT. Omówiono również możliwości wynikające z zastosowania modelu drożdżowego w poszukiwaniach nowych substancji leczniczych, jak i identyfikacji substancji neurotoksycznych.

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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model

Abstract: Preclinical proof-of-principle data demonstrate the high efficacy of IGHMBP2 gene therapy in the SMARD1 mouse model as well as in an in vitro model of the human disease.

Cited by 43 publications

References 26 publications

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Perspektywy terapii w polineuropatiach genetycznie uwarunkowanych

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