{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:48:50Z","timestamp":1792172930156,"version":"4.4.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fphar.2024.1454785","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T04:32:34Z","timestamp":1726806754000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["A quantitative systems pharmacology (QSP) platform for preclinical to clinical translation of in-vivo CRISPR-Cas therapy"],"prefix":"10.3389","volume":"15","author":[{"given":"Devam A.","family":"Desai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1002\/cpt.3000","article-title":"Clinical pharmacology and translational considerations in the development of CRISPR-based therapies","volume":"114","author":"Abdelhady","year":"2023","journal-title":"Clin. 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