Evidence map›Paper›PMID 39653070›Full record

ArticleMetabolic engineering2025

Metabolic engineering improves transduction efficiency and downstream vector isolation by altering the lipid composition of extracellular vesicle-enclosed AAV.

Paula Espinoza, Ming Cheng, Carrie Ng, Demitri de la Cruz, Elizabeth D Wasson, Deirdre M McCarthy, Pradeep G Bhide, Casey A Maguire, Miguel C Santoscoy

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Metabolic engineering, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

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

5 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Paula EspinozaHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
Ming ChengHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
Carrie NgHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
Demitri de la CruzHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
Elizabeth D WassonFSU Institute for Pediatric Rare Diseases, College of Medicine, Florida State University, Tallahassee, FL, USA.
Deirdre M McCarthyFSU Institute for Pediatric Rare Diseases, College of Medicine, Florida State University, Tallahassee, FL, USA.
Pradeep G BhideFSU Institute for Pediatric Rare Diseases, College of Medicine, Florida State University, Tallahassee, FL, USA.
Casey A MaguireHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: cmaguire@mgh.harvard.edu.
Miguel C SantoscoyHarvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: miguel.santoscoy@merck.com.

Funding

Enhanced gene delivery for CNS and sensory disordersR01DC017117 · NIDCD · MASSACHUSETTS GENERAL HOSPITAL · PI MAGUIRE, CASEY A · 2019 to 2023
$1.8M
NIDCD NIH HHS R01 DC017117
6 · The paper itself

Abstract

Adeno-associated viruses (AAV) are promising vectors for gene therapy due to their efficacy in vivo. However, there is room for improvement to address key limitations such as the pre-existing immunity to AAV in patients, high-dose toxicity, and relatively low efficiency for some cell types. This study introduces a metabolic engineering approach, using knockout of the enzyme phosphatidylserine synthase 1 (PTDSS1) to increase the abundance of extracellular vesicle-enclosed AAV (EV-AAV) relative to free AAV in the supernatant of producer cells, simplifying downstream purification processes. The lipid-engineered HEK293T-ΔPTDSS1 cell line achieved a 42.7-fold enrichment of EV-AAV9 compared to free AAV9 in the supernatant. The rational genetic strategy also led to a 300-fold decrease of free AAV in supernatant compared to wild-type HEK293T. The membrane-engineered EV-AAV9 (mEV-AAV9) showed unique envelope composition alterations, including cholesterol enrichment and improved transduction efficiency in human AC16 cardiomyocytes by 1.5-fold compared to conventional EV-AAV9 and by 11-fold compared to non-enveloped AAV9. Robust in-vivo transduction four weeks after intraparenchymal administration of mEV-AAV9 was observed in the murine brain. This study shows promise in the potential of lipid metabolic engineering strategies to improve the efficiency and process development of enveloped gene delivery vectors.

Indexed as

DependovirusExtracellular VesiclesGenetic VectorsLipidsMetabolic EngineeringTransduction, GeneticAnimalsHEK293 CellsHumansMiceLipidsDownstreamEV-AAVMembrane engineeringUpstream

Identifiers

PMID39653070
PMCPMC11850184

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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.