ArticleGene therapy2015
Gene therapy for rhesus monkeys heterozygous for LDL receptor deficiency by balloon catheter hepatic delivery of helper-dependent adenoviral vector.
Article in Gene therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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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.
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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.
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Who cites it
10 citing papers in PubMed.
- High-capacity adenoviral vector-mediated expression of an LDLR/transferrin chimeric protein in muscle reduces atherosclerosis in LdlrMolecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy.International journal of molecular sciences · 2020Review
- Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice.Gene therapy · 2019Article
- A Rabbit Model of Durable Transgene Expression in Jugular Vein to Common Carotid Artery Interposition Grafts.Journal of visualized experiments : JoVE · 2018Article
- Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.Journal of atherosclerosis and thrombosis · 2018Review
- Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management.Frontiers in pharmacology · 2018Review
- Gene therapy with helper-dependent adenoviral vectors: lessons from studies in large animal models.Virus genes · 2017Review
- Management of patients with familial hypercholesterolaemia.Nature reviews. Cardiology · 2015Review
- Liver-targeted gene therapy: Approaches and challenges.Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society · 2015Review
- Recent advances in gene therapy for lysosomal storage disorders.The application of clinical genetics · 2015Review
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Autosomal dominant familial hypercholesterolemia (FH) is a monogenic life-threatening disease. We tested the efficacy of low-density lipoprotein receptor (LDLR) gene therapy using helper-dependent adenoviral vector (HDAd) in a nonhuman primate model of FH, comparing intravenous injection versus intrahepatic arterial injection in the presence of balloon catheter-based hepatic venous occlusion. Rhesus monkeys heterozygous for mutant LDLR gene (LDLR+/-) developed hypercholesterolemia while on a high-cholesterol diet. We treated them with HDAd-LDLR either by intravenous delivery or by catheter-based intrahepatic artery injection. Intravenous injection of ⩽1.1 × 10(12) viral particles (vp) kg(-1) failed to have any effect on plasma cholesterol. Increasing the dose to 5 × 10(12) vp kg(-1) led to a 59% lowering of the plasma cholesterol that lasted for 30 days before it returned to pre-treatment levels by day 40. A further increase in dose to 8.4 × 10(12) vp kg(-1) resulted in severe lethal toxicity. In contrast, direct hepatic artery injection following catheter-based hepatic venous occlusion enabled the use of a reduced HDAd-LDLR dose of 1 × 10(12) vp kg(-1) that lowered plasma cholesterol within a week, and reached a nadir of 59% pre-treatment level on days 20-48 after injection. Serum alanine aminotransferase remained normal until day 48 when it went up slightly and stayed mildly elevated on day 72 before it returned to normal on day 90. In this monkey, the HDAd-LDLR-induced trough of hypocholesterolemia started trending upward on day 72 and returned to pre-treatment levels on day 120. We measured the LDL apolipoprotein B turnover rate at 10 days before, and again 79 days after, HDAd-LDLR treatment in two monkeys that exhibited a cholesterol-lowering response. HDAd-LDLR therapy increased the LDL fractional catabolic rate by 78 and 50% in the two monkeys, coincident with an increase in hepatic LDLR mRNA expression. In conclusion, HDAd-mediated LDLR gene delivery to the liver using a balloon catheter occlusion procedure is effective in reversing hypercholesterolemia in a nonhuman primate FH model; however, the unsustainability of the hypocholesterolemic response during 3-4 months of follow up and heterogeneous response to the treatment remains a challenge.
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