ArticleMolecular therapy : the journal of the American Society of Gene Therapy2020
Split AAV-Mediated Gene Therapy Restores Ureagenesis in a Murine Model of Carbamoyl Phosphate Synthetase 1 Deficiency.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine.Gut · 2026Review
- The Role of Urea Cycle Functional Studies in Preclinical Research.Journal of inherited metabolic disease · 2026Review
- A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system.Disease models & mechanisms · 2025Article
- An oversized AAV8 vector to deliver CPS1.Molecular therapy. Nucleic acids · 2025Article
- Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.Molecular therapy. Nucleic acids · 2025Article
- Characterization and treatment monitoring of ureagenesis disorders using stable isotopes.npj metabolic health and disease · 2025Article
- Skeleton keys and Trojan horses: a review of therapeutic delivery to the brain.Frontiers in cell and developmental biology · 2025Review
- The therapeutic landscape of citrin deficiency.Journal of inherited metabolic disease · 2024Review
- Gene therapy for urea cycle defects: An update from historical perspectives to future prospects.Journal of inherited metabolic disease · 2024Review
- Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice.International journal of molecular sciences · 2022Article
- Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency.Molecular therapy. Nucleic acids · 2022Article
- CRISPR-Mediated Genomic Addition to CPS1 Deficient iPSCs is Insufficient to Restore Nitrogen Homeostasis.The Yale journal of biology and medicine · 2021Article
- New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis.Communications biology · 2021Article
- CPS1: Looking at an ancient enzyme in a modern light.Molecular genetics and metabolism · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) catalyzes the initial step of the urea cycle; bi-allelic mutations typically present with hyperammonemia, vomiting, ataxia, lethargy progressing into coma, and death due to brain edema if ineffectively treated. The enzyme deficiency is particularly difficult to treat; early recognition is essential to minimize injury to the brain. Even under optimal conditions, therapeutic interventions are of limited scope and efficacy, with most patients developing long-term neurologic sequelae. One significant encumberment to gene therapeutic development is the size of the CPS1 cDNA, which, at 4.5 kb, nears the packaging capacity of adeno-associated virus (AAV). Herein we developed a split AAV (sAAV)-based approach, packaging the large transgene and its regulatory cassette into two separate vectors, thereby delivering therapeutic CPS1 by a dual vector system with testing in a murine model of the disorder. Cps1-deficient mice treated with sAAVs survive long-term with markedly improved ammonia levels, diminished dysregulation of circulating amino acids, and increased hepatic CPS1 expression and activity. In response to acute ammonia challenging, sAAV-treated female mice rapidly incorporated nitrogen into urea. This study demonstrates the first proof-of-principle that sAAV-mediated therapy is a viable, potentially clinically translatable approach to CPS1 deficiency, a devastating urea cycle disorder.
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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.