Clinical Pharmacology and Translational Considerations in the Development of CRISPR‐Based Therapies

Abstract

Genome editing holds the potential for curative treatments of human disease, however, clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism, and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model‐informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from phase I investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here, we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR‐based investigational therapies in the clinic.

Development of a minimal PBPK-QSP modeling platform for LNP-mRNA based therapeutics to study tissue disposition and protein expression dynamics

“…We next attempted to identify mechanisms contributing to potential second peak in mRNA PK and its implication for PD response. LNP redistribution and recycling have been observed in LNP based therapies (Goel et al, 2020;Abdelhady et al, 2023) and the model provided a platform to study this effect in silico given the absence of mechanistic empirical data. Simulations indicated that this second peak is formed under fast recycling rates and slow reuptake rates.…”

“…The model also incorporates the recycling mechanism of mRNA loaded LNP to explore the impact of redistribution on PK dynamics. This model allows for in silico investigation of conditions necessary for generation of a second peak in mRNA PK as observed experimentally (Goel et al, 2020;Abdelhady et al, 2023). Simulations also show implications of the recycling on protein production within the context of a nonsecreted intracellular enzyme such as UGT.…”

Novel Therapeutic Modalities: The Future is Now

“…The unique mechanism of action of CRISPR therapy requires new approaches for clinical translation and dose selection. Abdelhady and colleagues review the current status of clinical pharmacology and translation in the CRISPR field, with an emphasis on a mechanistic, quantitative approach to address the uncertainties from other empirical approaches in clinical development and study design 23 …”

“…Abdelhady and colleagues review the current status of clinical pharmacology and translation in the CRISPR field, with an emphasis on a mechanistic, quantitative approach to address the uncertainties from other empirical approaches in clinical development and study design. 23 Physiologically-based PK (PBPK) and quantitative systems pharmacology (QSP) modeling approaches are also evolving to support development of novel modalities. Parra-Guillen et al 24 describe the development and application of a mechanistic PBPK model linked to tumor response to assess clinical response to an oncolytic virus.…”