Preclinical Evaluation of AAV8-R338L Gene Therapy for Hemophilia: Efficacy, Pharmacokinetics, Distribution, Excretion and Toxicity in Mouse Models and Non-human Primates.
Dehu Dou, Jing Lu, Deli Li, Fengxia He, Xi Zhu, Xuefeng Zhang, Xijing Chen
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引用次数: 0
Abstract
Background: VGB-R04, an investigational gene therapy employs an engineered AAV8 capsid-based vector to deliver a liver-specific expression cassette encoding the high-activity FIX Padua variant (R338L) of human coagulation factor IX for Hemophilia B. The pharmacodynamics, Pharmacokinetic, immunogenicity and safety of VGB-R04 needs to be evaluated for non-clinical research.
Methods: The pharmacodynamics, Pharmacokinetic, immunogenicity and safety study of VGB-R04 via intravenous injection in mice and cynomolgus monkeys were conducted to support an investigational new drug (IND) application. The endpoints included pharmacodynamic biomarkers, in-life measurements. Anti-AAV8 neutralizing antibodies and anti-hFIX Padua protein antibody test, viral shedding, and tissue bio-distribution were analyzed.
Results: The peak concentration was noted one hour after injection, subsequently exhibiting a distinct decline over time. The elimination rate of target genes in mouse blood exceeded that in cynomolgus monkeys. The concentration in liver tissues was indicating distinct liver tissue tropism. The elimination rate of target genes in mouse liver exceeded that in cynomolgus monkeys. The plasma concentration of hFIX Padua protein exhibited a dose-dependent elevation in mice. Cynomolgus monkeys exhibited significant elevation in plasma concentrations of hFIX Padua protein at 4 × 1013 vg/kg. Anti-AAV8 neutralizing antibodies can be detected in both species, but no antibodies against anti-hFIX Padua were seen in mice. The NOAEL were 8 × 1012 vg/kg in mice and 4 × 1013 vg/kg in monkeys.
Conclusion: The studies demonstrated the pharmacodynamic advantages, pharmacokinetic profile with target distribution and potential safety of VGB-R04 in mice and cynomolgus monkeys after a single administration. The results support the gene therapy for future clinical studies.
期刊介绍：
Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to:
-(pre)formulation engineering and processing-
computational biopharmaceutics-
drug delivery and targeting-
molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)-
pharmacokinetics, pharmacodynamics and pharmacogenetics.
Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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