A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system

Alterman, Julia F.; Godinho, Bruno M.D.C.; Hassler, Matthew R.; Ferguson, Chantal; Echeverria, Dimas; Sapp, Ellen; Haraszti, Reka A.; Coles, Andrew H.; Conroy, Faith; Miller, Rachael; Roux, Loïc; Yan, Paul; Knox, Emily G.; Turanov, Anton A.; King, R; Gernoux, Gwladys; Mueller, Christian; Gray‐Edwards, Heather L.; Moser, Richard P.; Bishop, Nina; Jaber, Samer M.; Gounis, Matthew J.; Sena‐Esteves, Miguel; Pai, Athma A.; DiFiglia, Marian; Aronin, Neil; Khvorova, Anastasia

doi:10.1038/s41587-019-0205-0

Cited by 155 publications

(262 citation statements)

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“…Eine Repression der Genexpression im gesamten Gehirn durch kleine interferierende RNAs (siRNA) ist bisher noch nicht erreicht worden. Präklinische Studien zeigen, dass durch die Injektion divalenter siRNA (di-siRNA), aus zwei vollständig chemisch modifizierten und verbundenen siRNAs in das Ventrikelsystem, eine ausgeprägte, 50-bis 90 %ige Reduktion der HTT-Expression im ZNS erreicht werden kann, auch ohne Verwendung viraler Vektoren [23]. Bei Verabreichung an Makaken zeigte der Ansatz eine gute und gleichmäßige Verteilung über die beiden Hemisphären und führte zu einer deutlichen nichtallelselektiven Reduktion des HTT.…”

Section: Divalente Sirna Als Eine Innovative Methodeunclassified

Genselektive Therapieansätze bei der Huntington-Krankheit

et al. 2020

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ZusammenfassungIn Deutschland leiden derzeit mindestens 8000, vermutlich aber sogar bis zu ca. 14.000 Menschen an einer klinisch apparenten („manifesten“) Huntington-Krankheit (HK). Zudem tragen schätzungsweise 24.000 Deutsche die der HK zugrunde liegende Mutation im Huntingtin-(HTT)-Gen und werden im Laufe ihres Lebens an der HK erkranken. Obwohl die HK eine seltene neurodegenerative Erkrankung ist, steht sie gegenwärtig im Fokus eines allgemeinen medizinischen Interesses: Klinische Studien, die eine rationale Basis für die Hoffnung bilden, das bislang unaufhaltsame, schicksalhafte Fortschreiten der Erkrankung bis zur vollständigen Pflegebedürftigkeit bremsen und – bei rechtzeitigem Behandlungsbeginn – eventuell sogar die klinische Manifestation der HK mitigieren zu können, haben begonnen. Diese innovativen Therapieansätze sind darauf ausgerichtet, die Nachbildung mutierter HTT-Gen-Produkte zu hemmen. Eine erste klinische Arzneimittelprüfung zum Nachweis der Wirksamkeit (Phase III) intrathekaler Antisense-Oligonukleotide (ASO, Wirkstoff RG6042) hat 2019 begonnen. Klinische Studien zu weiteren, alternativen Behandlungsansätze mit allelselektiven ASOs sowie zu gentherapeutischen Ansätzen mit RNA-Molekülen und Zinkfinger-Repressor-Komplexen stehen kurz bevor. In dem vorliegenden Artikel geben wir einen Überblick über die gegenwärtig diskutierten genselektiven Therapieansätze bei der HK.

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Section: Divalente Sirna Als Eine Innovative Methodeunclassified

Genselektive Therapieansätze bei der Huntington-Krankheit

et al. 2020

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“…In Europe, a prevalence of 3/100,000 is assumed, the highest prevalence occurs in Sicily with 9.8/100,000 affected islanders [6]. However, current studies show that the genotype frequency with intermediate (36)(37)(38)(39) and pathological (>39) expansion in the huntigtin gene (HTT) may be as high as 139/100,000 [7]. Genetically, HD belongs to the group of trinucleotide repeat expansion disorders.…”

Section: Genetics and Pathophyiology Of Huntington's Diseasementioning

confidence: 99%

“…While individuals with a CAG repeat length of less than 35 located on exon 1 of HTT remain asymptomatic, alleles with 40 or more repeats show full penetrance. Intermediate alleles (36)(37)(38)(39) bear an increased risk to develop HD. There is an inverse correlation between the age of onset, and the length of the CAG repeat expansion, whereby alleles with more than 70 repetitions always cause a manifestation in adolescence.…”

Section: Genetics and Pathophyiology Of Huntington's Diseasementioning

confidence: 99%

“…In the past, siRNA mediated suppression of gene expression was locally restricted due to rapid degradation and low diffusion of the constructs. Recently, sophisticated modification of siRNA using a phosphothioate backbone and a divalent siRNA conjugate enabled whole brain penetrance and a 6-month, dose-dependent suppression of htt in mice and monkeys after a single intraventricular injection [38]. These findings may pave the way for a more sophisticated htt-lowering approach due to a simplified dosing regimen.…”

Section: Divalent Sirna Mediated Huntingtin-lowering; the Future At Hmentioning

confidence: 99%

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Huntingtin Lowering Strategies

Marxreiter

Stemick

Kohl

2020

IJMS

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Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.

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“…For example, Dieguez-Hurtado et al [14] found that inactivating a transcription factor, RBPJ, post-natally alters pericyte function, causing vascular instability and lesions with some similarities to cerebral cavernous malformations, and greater injury after ischemic stroke. Another advance for manipulating the NVU and brain (experimentally and therapeutically) is the finding by Alterman et al [15] that a single CSF injection of divalent small interfering RNAs is effective in reducing huntingtin expression (mRNA and protein) throughout the mouse brain, with effects lasting for at least 6 months. They had similar results in cynomolgus macaques.…”

Section: Toolsmentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

Keep

Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system

Abstract: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Cited by 155 publications

References 50 publications

Genselektive Therapieansätze bei der Huntington-Krankheit

Genselektive Therapieansätze bei der Huntington-Krankheit

Huntingtin Lowering Strategies

This was the year that was: brain barriers and brain fluid research in 2019

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