Evidence map›Paper›PMID 37409482›Full record

ArticleCirculation2023

Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart.

Xisheng Li, Sabrina La Salvia, Yaxuan Liang, Marta Adamiak, Erik Kohlbrenner, Dongtak Jeong, Elena Chepurko, Delaine Ceholski, Estrella Lopez-Gordo, Seonghun Yoon and 14 more

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

Article in Circulation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.

0numbers the graph read from it
0cells of the map it votes in
57citing papers in PubMed
11.5field-weighted citation impact, top 1% 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

57 citing papers in PubMed, 75 citations in OpenAlex.

  1. Review
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  9. Article
  10. Past, Present and Future of Regenerative Gene Therapy for Ischemic Heart Failure.Journal of cardiovascular translational research · 2026
    Review
  11. EV-Encapsulated Mitochondrial miRNAs: Enhancing Cardiomyocyte Bioenergetics.International journal of molecular sciences · 2026
    Review
  12. Article
  13. Review
  14. Review
  15. Review
  16. Gene therapy for cardiac arrhythmias.Nature reviews. Cardiology · 2026
    Review
  17. Review
  18. Article
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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

24 authors at 9 institutions in 5 countries.

Xisheng Li *Cardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Sabrina La Salvia *Cardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Yaxuan Liang *Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, China (Y.L.).
Marta AdamiakCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Erik KohlbrennerCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Dongtak JeongDepartment of Molecular and Life Science, College of Science and Convergence Technology, Hanyang University-ERICA, Ansan, South Korea (D.J.).
Elena ChepurkoCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Delaine CeholskiCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Estrella Lopez-GordoCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Seonghun YoonCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Prabhu MathiyalaganBenthos Prime Central, Houston, TX (P.M.).ORCID 0000-0002-8202-9266
Neha AgarwalCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0002-3792-6750
Divya JhaCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Shweta LodhaCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
George DaaboulNanoView Biosciences, Boston, MA (G.D.).
Anh PhanCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Nikhil RaisinghaniCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.
Shihong ZhangCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0002-9661-1089
Lior ZangiCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0002-6153-9857
Edgar Gonzalez-KozlovaDepartment of Oncological Sciences (E.G.-K.), Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0002-6948-0626
Nicole DuboisDepartment of Cell, Developmental and Regenerative Biology (N. Dubois), Icahn School of Medicine at Mount Sinai, New York, NY.
Navneet DograDepartment of Pathology and Laboratory Medicine (N. Dogra), Icahn School of Medicine at Mount Sinai, New York, NY.
Roger J HajjarGene and Cell Therapy Institute, Massachusetts General Brigham, Boston (R.J.H.).ORCID 0000-0003-2522-1507
Susmita SahooCardiovascular Research Institute (X.L., S.L.S., M.A., E.C., D.C., E.L.-G., S.Y., N.A., D.J., S.L., A.P., N.R., S.Z., L.Z., S.S.), Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0002-7279-1564
Icahn School of Medicine at Mount Sinai · USAnna Needs Neuroblastoma Answers · USBeijing Normal University · CNBoston Biomedical Research Institute · USChild Health and Development Institute · USHanyang University · KRPrecision BioSciences (United States) · USPrime University · BDSpark Therapeutics (United States) · US

Funding

Extracellular Vesicle-Encapsulated AAVs for Therapeutic Gene Delivery to the HeartR01HL148786 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Kiyotake Ishikawa, Susmita Sahoo · 2019 to 2026
$4.1M
Therapeutic Mechanisms of Human CD34 ExosomesR01HL124187 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI SAHOO, SUSMITA · 2014 to 2018
$2.1M
Circulating Extracellular Vesicles in the Pathogenesis of Type 1 DiabetesR01DK125856 · NIDDK · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · PI SAHOO, SUSMITA, VASAVADA, RUPANGI C · 2021 to 2024
$1.8M
Dysregulated Adenosine Methylation of mRNA as a Novel Mechanism of Heart FailureR01HL140469 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SAHOO, SUSMITA · 2018 to 2021
$1.7M
NHLBI NIH HHS R01 HL124187NHLBI NIH HHS R01 HL140469NHLBI NIH HHS R01 HL148786NIDDK NIH HHS R01 DK125856
6 · The paper itself

Abstract

backgroundAdeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use is preexisting neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction, and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance.

methodsWe developed a 2-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs. We compared the gene delivery and therapeutic efficacy of EV-AAVs with an equal titer of free AAVs in the presence of NAbs, both in vitro and in vivo. In addition, we investigated the mechanism of EV-AAV uptake in human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and mouse models in vivo using a combination of biochemical techniques, flow cytometry, and immunofluorescence imaging.

resultsUsing cardiotropic AAV serotypes 6 and 9 and several reporter constructs, we demonstrated that EV-AAVs deliver significantly higher quantities of genes than AAVs in the presence of NAbs, both to human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and to mouse hearts in vivo. Intramyocardial delivery of EV-AAV9-sarcoplasmic reticulum calcium ATPase 2a to infarcted hearts in preimmunized mice significantly improved ejection fraction and fractional shortening compared with AAV9-sarcoplasmic reticulum calcium ATPase 2a delivery. These data validated NAb evasion by and therapeutic efficacy of EV-AAV9 vectors. Trafficking studies using human induced pluripotent stem cell-derived cells in vitro and mouse hearts in vivo showed significantly higher expression of EV-AAV6/9-delivered genes in cardiomyocytes compared with noncardiomyocytes, even with comparable cellular uptake. Using cellular subfraction analyses and pH-sensitive dyes, we discovered that EV-AAVs were internalized into acidic endosomal compartments of cardiomyocytes for releasing and acidifying AAVs for their nuclear uptake.

conclusionsTogether, using 5 different in vitro and in vivo model systems, we demonstrate significantly higher potency and therapeutic efficacy of EV-AAV vectors compared with free AAVs in the presence of NAbs. These results establish the potential of EV-AAV vectors as a gene delivery tool to treat heart failure.

Indexed as

Extracellular VesiclesInduced Pluripotent Stem CellsAnimalsAntibodies, NeutralizingDependovirusGenetic VectorsHumansMiceSarcoplasmic Reticulum Calcium-Transporting ATPasesAntibodies, NeutralizingSarcoplasmic Reticulum Calcium-Transporting ATPasesextracellular vesiclesgenetic therapy

Identifiers

PMID37409482
PMCPMC12462899
OpenAlexW4383302672

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Registered trials

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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.