A quantitative systems pharmacology (QSP) platform for preclinical to clinical translation of <i>in-vivo</i> CRISPR-Cas therapy.

ABSTRACT: Background: In-vivo CRISPR Cas genome editing is a complex therapy involving lipid nanoparticle (LNP), messenger RNA (mRNA), and single guide RNA (sgRNA). This novel modality requires prior modeling to predict dose-exposure-response relationships due to limited information on sgRNA and mRNA biodistribution. This work presents a QSP model to characterize, predict, and translate the Pharmacokinetics/Pharmacodynamics (PK/PD) of CRISPR therapies from preclinical species (mouse, non-human primate (NHP)) to humans using two case studies: transthyretin amyloidosis and LDL-cholesterol reduction. Methods: PK/PD data were sourced from literature. The QSP model incorporates mechanisms post-IV injection: 1) LNP binding to opsonins in liver vasculature; 2) Phagocytosis into the Mononuclea

SUBMITTER: Desai DA 

PROVIDER: S-EPMC11449743 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature