Clinical trials and promising preclinical applications of CRISPR/Cas gene editing

Çerçi, Barış; Uzay, İhsan Alp; Kara, Mustafa Kemal; Dinçer, Pervin

doi:10.1016/j.lfs.2022.121204

Cited by 9 publications

(7 citation statements)

References 257 publications

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“…Although ex vivo CRISPR therapies have had an initial head start in development, in vivo CRISPR therapies are becoming an increasingly important component of the genome editing clinical landscape. A recent 2023 review, 3 provides a comprehensive tabulated summary of CRISPR clinical trials and summarizes 28 clinical trials investigating ex vivo therapies and 6 clinical trials investigating in vivo CRISPR therapies.…”

Section: Figurementioning

confidence: 99%

“…This approach can potentially enhance persistence of allogeneic cells; however, lack of HLA expression renders the cells as targets for host NK cells 60 . Several allogeneic cell therapies implementing β‐2 microglobulin disruption are being studied in individual clinical trials 3 . Although a systematic, cross‐study evaluation of the effect of β‐2 microglobulin disruption on CKs has yet to be conducted, the allogeneic anti‐CD19 CAR‐T therapy CTX110 (that implements CRISPR‐mediated β‐2 microglobulin disruption) was reported to decline below limit of detection in patients by 3–4 weeks 78…”

Section: Ex Vivo Crispr Therapiesmentioning

confidence: 99%

“…CRISPR therapies may be subcategorized into both in vivo and ex vivo applications 2,3 . For in vivo applications, CRISPR therapies are administered locally or systemically to the patient.…”

Section: Figurementioning

confidence: 99%

“…A formulation based upon the lipid nanoparticle (LNP) was proposed to fulfill these criteria, and an LNP‐based formulation was ultimately used for NTLA‐2001, an investigational therapy and the first systemically administered in vivo CRISPR/Cas9‐based therapy evaluated in the clinic 8 . Although systemically administered in vivo CRISPR‐based therapies rely upon both AAV‐ and LNP‐based delivery vehicles, the LNP predominates the clinical investigation landscape at the time of writing 3 ; the primary focus in the sections that follow is accordingly upon systemic administration of the LNP‐based system.…”

Section: In Vivo Crispr Therapiesmentioning

confidence: 99%

“…CRISPR therapies may be subcategorized into both in vivo and ex vivo applications. 2,3 For in vivo applications, CRISPR therapies are administered locally or systemically to the patient. In the ex vivo setting, a particular cell type is typically first isolated and expanded prior to exposure to the CRISPR therapy; the edited cells are then introduced to the patient.…”

mentioning

confidence: 99%

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

Abdelhady

Phillips

et al. 2023

Clin Pharma and Therapeutics

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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.

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Section: Figurementioning

confidence: 99%

Section: Ex Vivo Crispr Therapiesmentioning

confidence: 99%

“…CRISPR therapies may be subcategorized into both in vivo and ex vivo applications 2,3 . For in vivo applications, CRISPR therapies are administered locally or systemically to the patient.…”

Section: Figurementioning

confidence: 99%

Section: In Vivo Crispr Therapiesmentioning

confidence: 99%

mentioning

confidence: 99%

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

Abdelhady

Phillips

et al. 2023

Clin Pharma and Therapeutics

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Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

Jia,

Wang,

et al. 2023

Advanced Materials

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Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, we concluded different strategies to efficiently deliver nucleic acid delivery from LNPs and investigated their mechanisms. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, we discussed the issues that are necessary to be approached in the clinical translation of LNPs, which we hope will shed light on the development of LNP nucleic acid drugs.This article is protected by copyright. All rights reserved

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Tumor Microenvironment‐Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma

He,

Li,

et al. 2024

Advanced Science

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Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR‐Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.

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Clinical trials and promising preclinical applications of CRISPR/Cas gene editing

Cited by 9 publications

References 257 publications

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

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

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

Tumor Microenvironment‐Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma

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