Evidence map›Paper›PMID 38445045›Full record

ArticleMolecular therapy. Methods & clinical development2024

Biodistribution and safety of a single rAAV3B-AAT vector for silencing and replacement of alpha-1 antitrypsin in

Meghan Blackwood, Alisha M Gruntman, Qiushi Tang, Debora Pires-Ferreira, Darcy Reil, Oleksandr Kondratov, Damien Marsic, Sergei Zolotukhin, Gwladys Gernoux, Allison M Keeler and 2 more

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

Article in Molecular therapy. Methods & clinical development, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
1.7field-weighted citation impact, top 17% 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

2 citing papers in PubMed, 3 citations in OpenAlex.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 5 institutions in 4 countries.

Meghan BlackwoodHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Alisha M GruntmanHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Qiushi TangHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Debora Pires-FerreiraHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Darcy ReilHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Oleksandr KondratovDivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.
Damien MarsicDivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.
Sergei ZolotukhinDivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.
Gwladys GernouxNantes Université, CHU de Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR 1089, 44200 Nantes, France.
Allison M KeelerHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Christian MuellerGenomic Medicine Unit, Sanofi, Waltham, MA 02451, USA.
Terence R FlotteHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
University of Massachusetts Chan Medical School · USUniversity of Florida · USCenter for Genomic Science · ITInserm · FRTufts University · US

Funding

Vector Immunology CoreP01HL158506 · NHLBI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Terence R. Flotte · 2021 to 2026
$19.5M
Viral Vector CoreP01HL131471 · NHLBI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI FLOTTE, TERENCE R. · 2016 to 2020
$11.3M
Nuclease free gene editing approaches to treat alpha-1 antitrypsin diseaseR01DK098252 · NIDDK · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI FLOTTE, TERENCE R. · 2013 to 2022
$3.0M
NHLBI NIH HHS P01 HL131471NHLBI NIH HHS P01 HL158506NIDDK NIH HHS R01 DK098252
6 · The paper itself

Abstract

Alpha-1 antitrypsin deficiency (AATD) is characterized by both chronic lung disease due to loss of wild-type AAT (M-AAT) antiprotease function and liver disease due to toxicity from delayed secretion, polymerization, and aggregation of misfolded mutant AAT (Z-AAT). The ideal gene therapy for AATD should therefore comprise both endogenous Z-AAT suppression and M-AAT overexpression. We designed a dual-function rAAV3B (df-rAAV3B) construct, which was effective at transducing hepatocytes, resulting in a considerable decrease of Z-AAT levels and safe M-AAT augmentation in mice. We optimized df-rAAV3B and created two variants, AAV3B-E12 and AAV3B-G3, to simultaneously enhance the concentration of M-AAT in the bloodstream to therapeutic levels and silence endogenous AAT liver expression in cynomolgus monkeys. Our results demonstrate that AAV3b-WT, AAV3B-E12, and AAV3B-G3 were able to transduce the monkey livers and achieve high M-AAT serum levels efficiently and safely. In this nondeficient model, we did not find downregulation of endogenous AAT. However, the dual-function vector did serve as a potentially "liver-sparing" alternative for high-dose liver-mediated AAT gene replacement in the context of underlying liver disease.

Indexed as

AAV3BAAV gene therapyalpha-1 antitrypsin deficiencybiodistributiongene silencingmiRNApreclinical

Identifiers

PMID38445045
PMCPMC10914479
OpenAlexW4391345748

What OpenQuestion holds

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LicenceCC BY
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.