A quantitative systems pharmacology (QSP) platform for preclinical to clinical translation of in-vivo CRISPR-Cas therapy
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. Thi...
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Published in | Frontiers in pharmacology Vol. 15; p. 1454785 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
2024
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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 Mononuclear Phagocytotic System (MPS); 3) LNP internalization via endocytosis and LDL receptor-mediated endocytosis in the liver; 4) Cellular internalization and transgene product release; 5) mRNA and sgRNA disposition via exocytosis and clathrin-mediated endocytosis; 6) Renal elimination of LNP and sgRNA; 7) Exonuclease degradation of sgRNA and mRNA; 8) mRNA translation into Cas9 and RNP complex formation for gene editing. Monte-Carlo simulations were performed for 1000 subjects and showed a reduction in serum TTR.
The rate of internalization in interstitial layer was 0.039 1/h in NHP and 0.007 1/h in humans. The rate of exocytosis was 6.84 1/h in mouse, 2690 1/h in NHP, and 775 1/h in humans. Pharmacodynamics were modeled using an indirect response model, estimating first-order degradation rate (0.493 1/d) and TTR reduction parameters in NHP.
The QSP model effectively characterized biodistribution and dose-exposure relationships, aiding the development of these novel therapies. The utility of platform QSP model can be paramount in facilitating the discovery and development of these novel agents. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2024.1454785 |