Evidence map›Paper›PMID 30143435›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2018

Transvascular Delivery of Hydrophobically Modified siRNAs: Gene Silencing in the Rat Brain upon Disruption of the Blood-Brain Barrier.

Bruno M D C Godinho, Nils Henninger, James Bouley, Julia F Alterman, Reka A Haraszti, James W Gilbert, Ellen Sapp, Andrew H Coles, Annabelle Biscans, Mehran Nikan and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
3.1field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 80 citations in OpenAlex.

  1. Review
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  9. Nucleic acid drug vectors for diagnosis and treatment of brain diseases.Signal transduction and targeted therapy · 2023
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 1 country.

Bruno M D C GodinhoRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: bruno.godinho@umassmed.edu.
Nils HenningerDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01605, USA.
James BouleyDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Julia F AltermanRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Reka A HarasztiRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
James W GilbertRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Ellen SappDepartment of Neurology, Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
Andrew H ColesRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Annabelle BiscansRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mehran NikanRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Dimas EcheverriaRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Marian DiFigliaDepartment of Neurology, Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
Neil AroninRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Anastasia KhvorovaRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: anastasia.khvorova@umassmed.edu.
University of Massachusetts Chan Medical School · USMaineGeneral Medical Center · USMassachusetts General Hospital · US

Funding

Expanding the chemical diversity of therapeutic oligonucleotides to treat neurodegenerative disordersR01NS104022 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ANASTASIA KHVOROVA · 2017 to 2026
$6.0M
Inhibiting axon degeneration in a mouse model of acute brain injury through deletion of Sarm1K08NS091499 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI HENNINGER, NILS · 2016 to 2020
$919k
Mid-Scale RNA Synthesis, Purification and Quality Control SystemS10OD020012 · OD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI KHVOROVA, ANASTASIA · 2015 to 2015
$563k
NIH HHS S10 OD020012NINDS NIH HHS K08 NS091499NINDS NIH HHS R01 NS104022
6 · The paper itself

Abstract

Effective transvascular delivery of therapeutic oligonucleotides to the brain presents a major hurdle to the development of gene silencing technologies for treatment of genetically defined neurological disorders. Distribution to the brain after systemic administrations is hampered by the low permeability of the blood-brain barrier (BBB) and the rapid clearance kinetics of these drugs from the blood. Here we show that transient osmotic disruption of the BBB enables transvascular delivery of hydrophobically modified small interfering RNA (hsiRNA) to the rat brain. Intracarotid administration of 25% mannitol and hsiRNA conjugated to phosphocholine-docosahexanoic acid (PC-DHA) resulted in broad ipsilateral distribution of PC-DHA-hsiRNAs in the brain. PC-DHA conjugation enables hsiRNA retention in the parenchyma proximal to the brain vasculature and enabled active internalization by neurons and astrocytes. Moreover, transvascular delivery of PC-DHA-hsiRNAs effected Htt mRNA silencing in the striatum (55%), hippocampus (51%), somatosensory cortex (52%), motor cortex (37%), and thalamus (33%) 1 week after administration. Aside from mild gliosis induced by osmotic disruption of the BBB, transvascular delivery of PC-DHA-hsiRNAs was not associated with neurotoxicity. Together, these findings provide proof-of-concept that temporary disruption of the BBB is an effective strategy for the delivery of therapeutic oligonucleotides to the brain.

Indexed as

AnimalsAstrocytesBlood-Brain BarrierBrainCarotid ArteriesDocosahexaenoic AcidsGene SilencingGenetic TherapyHumansHuntingtin ProteinHydrophobic and Hydrophilic InteractionsMannitolNeuronsPhosphorylcholineRatsRNA, Small InterferingDocosahexaenoic AcidsHtt protein, ratHuntingtin ProteinMannitolPhosphorylcholineRNA, Small Interferinghyperosmolar mannitolintracarotid injectionosmotic disruptionRNA interferencetherapeutic oligonucleotide

Identifiers

PMID30143435
PMCPMC6225091
OpenAlexW2887624337

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.