I05 Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of huntington disease minipigs mediated by AAV5-MIHTT gene therapy

Valls, Astrid; Brouwers, Cynthia; Pintauro, Roberta; Snapper, Jolanda; Bohuslavová, Božena; Sogorb-Gonzalez, Marina; Fodale, Valentina; Bresciani, Alberto; Ellederová, Zdeňka; Blits, Bas; Deventer, Sander van; Evers, Melvin M.; Konstantinova, Pavlina

doi:10.1136/jnnp-2018-ehdn.241

Cited by 2 publications

(2 citation statements)

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“…In HD animal models, a single intrastriatal infusion of rAAV5- miHtt resulted in dose-dependent increases in miHTT levels in the deep brain structures associated with HD pathology with subsequent decreases in Htt mRNA and no evidence of off-target effects. 21 , 22 , 23 , 24 , 25 Levels of transgene expression correlated with vector DNA copy numbers (VCNs) from the same brain region, and reductions in Htt mRNA were accompanied by HTT protein reductions lasting at least 12 months in HD mice 21 and minipigs. 23 In HD mice, significant reductions in HTT aggregates were associated with reversed neuron dysfunction prior to neuron death, improved HD symptoms, and extended survival.…”

Section: Introductionmentioning

confidence: 99%

Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

Zancanella¹,

Vallès²,

Liefhebber³

et al. 2023

Molecular Therapy - Nucleic Acids

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Section: Introductionmentioning

confidence: 99%

Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

Zancanella¹,

Vallès²,

Liefhebber³

et al. 2023

Molecular Therapy - Nucleic Acids

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“…Currently, clinical trials are underway for RNAis such as AMT-130. AMT-130-treated transgenic minipig HD models displayed a significant reduction in mHtt aggregates by 68% and 47% in the striatum and cortex, respectively, 6months post-treatment (48). Gene targeting therapy for FXTAS is still under study via reductions in toxic FMR1 mRNA and FMRP.…”

Section: Gene Targeting Therapy -Reducing Protein and Mrna Expressionmentioning

confidence: 99%

The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

Alvarez-Amado¹

2020

Preprint

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Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS

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I05 Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of huntington disease minipigs mediated by AAV5-MIHTT gene therapy

Cited by 2 publications

References 0 publications

Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

Proof-of-concept study for liver-directed miQURE technology in a dyslipidemic mouse model

The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

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