ArticleHepatology (Baltimore, Md.)2021
Promoterless, Nuclease-Free Genome Editing Confers a Growth Advantage for Corrected Hepatocytes in Mice With Methylmalonic Acidemia.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers, 1 of them a synthesis that pooled it.
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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.
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.
Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Contributions from medical geneticists in clinical trials of genetic therapies: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2023Guideline
- First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study.Gene therapy · 2026Trial
- Rapamycin nanoparticles mitigate anti-AAV antibody formation in a mouse model of ornithine transcarbamylase deficiency.Molecular therapy. Advances · 2026Article
- Gene therapy for liver diseases: methods, challenges and opportunities.Journal of nanobiotechnology · 2026Review
- Review
- Article
- Article
- The deLIVERed promises of gene therapy: Past, present, and future of liver-directed gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- AAV-mediated genome editing is influenced by the formation of R-loops.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Nuclease-free precise genome editing corrects MECP2 mutations associated with Rett syndrome.Frontiers in genome editing · 2024Article
- Review
- Gene therapy for urea cycle defects: An update from historical perspectives to future prospects.Journal of inherited metabolic disease · 2024Review
- State-of-the-art 2023 on gene therapy for phenylketonuria.Journal of inherited metabolic disease · 2024Review
- CRISPR-Cas9-mediated somatic correction of a one-base deletion in the Ugt1a gene ameliorates hyperbilirubinemia in Crigler-Najjar syndrome mice.Molecular therapy. Methods & clinical development · 2023Article
- Genome editing without nucleases confers proliferative advantage to edited hepatocytes and corrects Wilson disease.JCI insight · 2023Article
- Investigating the hepatoprotective potentiality of marine-derived steroids as promising inhibitors of liver fibrosis.RSC advances · 2023Article
- Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia.Journal of inherited metabolic disease · 2023Review
- Genome editing usingMolecular therapy. Methods & clinical development · 2023Article
- Intrathymic AAV delivery results in therapeutic site-specific integration at TCR loci in mice.Blood · 2023Article
- Gene therapy for liver diseases - progress and challenges.Nature reviews. Gastroenterology & hepatology · 2023Review
Corrections and comments
- Erratum issuedErratum.2022
Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
BACKGROUND AND
aimsAdeno-associated viral (AAV) gene therapy has shown great promise as an alternative treatment for metabolic disorders managed using liver transplantation, but remains limited by transgene loss and genotoxicity. Our study aims to test an AAV vector with a promoterless integrating cassette, designed to provide sustained hepatic transgene expression and reduced toxicity in comparison to canonical AAV therapy. APPROACH AND
resultsOur AAV vector was designed to insert a methylmalonyl-CoA mutase (MMUT) transgene into the 3' end of the albumin locus and tested in mouse models of methylmalonic acidemia (MMA). After neonatal delivery, we longitudinally evaluated hepatic transgene expression, plasma levels of methylmalonate, and the MMA biomarker, fibroblast growth factor 21 (Fgf21), as well as integration of MMUT in the albumin locus. At necropsy, we surveyed for AAV-related hepatocellular carcinoma (HCC) in all treated MMA mice and control littermates. AAV-mediated genome editing of MMUT into the albumin locus resulted in permanent hepatic correction in MMA mouse models, which was accompanied by decreased levels of methylmalonate and Fgf21, and improved survival without HCC. With time, levels of transgene expression increased and methylmalonate progressively decreased, whereas the number of albumin-MMUT integrations and corrected hepatocytes in MMA mice increased, but not in similarly treated wild-type animals. Additionally, expression of MMUT in the setting of MMA conferred a selective growth advantage upon edited cells, which potentiates the therapeutic response.
conclusionsIn conclusion, our findings demonstrate that AAV-mediated, promoterless, nuclease-free genome editing at the albumin locus provides safe and durable therapeutic benefit in neonatally treated MMA mice.
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Registered trials
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.