To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mA …

With the recent difficulties in selecting safe and effective doses for AAV-based gene therapies seen clinically, PBPK models allowing for in-depth exploration of AAV pharmacology could be the key the field needs to treat these unmet disease populations.

2024年1月1日 · Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies.

2021年3月1日 · The most promising variant, AAV-PHP.B, delivered more than 40-fold AAV genomes to the CNS compared to AAV9 and transduced >50% of all neurons and astrocytes sampled after IV dosing in adult C57BL/6 mice.

2023年7月31日 · Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist.

2023年7月31日 · When characterizing the PK of rAAV-mediated gene therapy, the vector and/or transgene DNA, transgene mRNA, and protein are the main analytes of interest and can inform the disposition of AAV and its downstream biological events, and the threshold levels associated with efficacy and safety of AAV.

Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies.

Download scientific diagram | Example schematic of systemic AAV PBPK distribution with suggested applicable compartments based on AAV tropism and frequently targeted tissues of AAV therapy....

2023年10月17日 · Example schematic of systemic AAV PBPK distribution with suggested applicable compartments based on AAV tropism and frequently target tissues of AAV therapy. Applicable modeling parameters as...

2024年1月1日 · To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice.