Evidence map›Paper›PMID 39336779›Full record

ArticleGenes2024

Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy.

Debora Pires-Ferreira, Darcy Reil, Qiushi Tang, Meghan Blackwood, Thomas Gallagher, Allison M Keeler, Jessica A Chichester, Kristin K Vyhnal, Jane A Lindborg, Janet Benson and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genes, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

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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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

13 authors.

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.
Qiushi TangHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Meghan BlackwoodHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Thomas GallagherHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.ORCID 0000-0001-6381-6902
Allison M KeelerHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-5202-4616
Jessica A ChichesterGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.ORCID 0000-0001-7879-120X
Kristin K VyhnalLovelace Biomedical Research Institute, Albuquerque, NM 87108, USA.
Jane A LindborgLovelace Biomedical Research Institute, Albuquerque, NM 87108, USA.
Janet BensonLovelace Biomedical Research Institute, Albuquerque, NM 87108, USA.
Dongtao FuDepartment of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
Terence R FlotteHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-8255-0588
Alisha M GruntmanHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

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
NHLBI NIH HHS P01 HL131471NHLBI NIH HHS P01 HL158506NIH HHS 1P01HL131471-22A1NIH HHS 1P01HL158506-26A1ORFDO NIH HHS 75N99019D00017
6 · The paper itself

Abstract

BACKGROUND/

objectivesα-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species.

methodsIn this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 10

resultsWe found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels.

conclusionsOur results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 10

Indexed as

alpha 1-Antitrypsinalpha 1-Antitrypsin DeficiencyDependovirusGenetic TherapyGenetic VectorsAnimalsHumansMaleMuscle, Skeletalalpha 1-AntitrypsinAATD gene therapyalpha-1 anti-trypsinbiodistributionpre-clinical studyrAAV gene therapyrAAV safety

Identifiers

PMID39336779
PMCPMC11431094

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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.