Metal Ion Signaling in Biomedicine DOI Creative Commons
Raphaël Rodriguez, Sebastian Müller, Ludovic Colombeau

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species defined by their genomes, and differences between individuals within a given species directly result from variations in genetic codes. While alterations give rise to disease-causing acquisitions cell identities, it is now well-established biochemical imbalances also lead cellular dysfunction diseases. Specifically, nongenetic chemical events orchestrate metabolism transcriptional programs govern functional identity. Thus, signaling, which broadly defines the conversion extracellular signals into intracellular changes, contribute acquisition diseased states. Metal ions exhibit unique properties be exploited cell. For instance, metal maintain ionic balance cell, coordinate amino acid residues or nucleobases altering folding function biomolecules, catalyze reactions. metals essential signaling effectors normal physiology disease. Deciphering ion challenging endeavor illuminate pathways targeted for therapeutic intervention. Here, we review key processes where play roles describe how targeting has been instrumental dissecting biochemistry this led development effective strategies.

Language: Английский

Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins DOI Creative Commons
Samagya Banskota, Aditya Raguram, Susie Suh

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(2), P. 250 - 265.e16

Published: Jan. 1, 2022

Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package base editor or Cas9 ribonucleoproteins. By engineering VLPs overcome cargo packaging, release, localization bottlenecks, we developed fourth-generation eVLPs mediate efficient several primary mouse human cell types. Using different glycoproteins alters their cellular tropism. Single injections into mice support therapeutic levels multiple tissues, reducing serum Pcsk9 78% following 63% liver editing, partially restoring visual function a model genetic blindness. In vitro off-target from was virtually undetected, an improvement AAV plasmid delivery. These results establish promising vehicles for macromolecule combine key both viral nonviral

Language: Английский

Citations

415
CRISPR/Cas9 therapeutics: progress and prospects DOI Creative Commons
Tianxiang Li, Yanyan Yang, Hongzhao Qi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 16, 2023

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology is the ideal tool of future for treating diseases by permanently correcting deleterious base mutations or disrupting disease-causing genes with great precision and efficiency. A variety efficient Cas9 variants derivatives have been developed to cope complex genomic changes that occur during diseases. However, strategies effectively deliver CRISPR system diseased cells in vivo are currently lacking, nonviral vectors target recognition functions may be focus research. Pathological physiological resulting from disease onset expected serve as identifying factors targeted delivery targets gene editing. Diseases both varied complex, choice appropriate methods different important. Meanwhile, there still many potential challenges identified when targeting CRISPR/Cas9 treatment. This paper reviews current developments three aspects, namely, type, vector, characteristics. Additionally, this summarizes successful examples clinical trials finally describes possible problems associated applications.

Language: Английский

Citations

321
Therapeutic in vivo delivery of gene editing agents DOI Creative Commons
Aditya Raguram, Samagya Banskota, David R. Liu

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2806 - 2827

Published: July 1, 2022

In vivo gene editing therapies offer the potential to treat root causes of many genetic diseases. Realizing promise therapeutic in requires ability safely and efficiently deliver agents relevant organs tissues vivo. Here, we review current delivery technologies that have been used enable editing, including viral vectors, lipid nanoparticles, virus-like particles. Since no single modality is likely be appropriate for every possible application, compare benefits drawbacks each method highlight opportunities future improvements.

Language: Английский

Citations

297
Current applications and future perspective of CRISPR/Cas9 gene editing in cancer DOI Creative Commons
Siwei Wang, Chao Gao,

Yi-Min Zheng

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Feb. 21, 2022

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR) system provides adaptive immunity against plasmids and phages in prokaryotes. This inspires the development of a powerful genome engineering tool, CRISPR/CRISPR-associated nuclease 9 (CRISPR/Cas9) editing system. Due to its high efficiency precision, CRISPR/Cas9 technique has been employed explore functions cancer-related genes, establish tumor-bearing animal models probe drug targets, vastly increasing our understanding cancer genomics. Here, we review current status gene technology oncological research. We first explain basic principles introduce several new CRISPR-based modes. next detail rapid progress CRISPR screening revealing tumorigenesis, metastasis, resistance mechanisms. In addition, delivery vectors finally demonstrate potential enhance effect adoptive T cell therapy (ACT) reduce adverse reactions.

Language: Английский

Citations

265
CRISPR-based genome editing through the lens of DNA repair DOI Creative Commons

Tarun S. Nambiar,

Lou Baudrier,

Pierre Billon

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(2), P. 348 - 388

Published: Jan. 1, 2022

Language: Английский

Citations

155
In vivo hematopoietic stem cell modification by mRNA delivery DOI
Laura Breda, Tyler E. Papp, Michael Triebwasser

et al.

Science, Journal Year: 2023, Volume and Issue: 381(6656), P. 436 - 443

Published: July 27, 2023

Hematopoietic stem cells (HSCs) are the source of all blood over an individual's lifetime. Diseased HSCs can be replaced with gene-engineered or healthy through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP-messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA is targeted to cell factor receptor (CD117) on HSCs. Delivery anti-human CD117/LNP-based editing system yielded near-complete correction hematopoietic sickle cells. Furthermore, in vivo delivery pro-apoptotic PUMA (p53 up-regulated modulator apoptosis) CD117/LNP affected function permitted nongenotoxic conditioning for HSCT. The ability target offers regimen HSCT, this platform could basis genome cure genetic disorders, which would abrogate need

Language: Английский

Citations

153
In vivo somatic cell base editing and prime editing DOI Creative Commons
Gregory A. Newby, David R. Liu

Molecular Therapy, Journal Year: 2021, Volume and Issue: 29(11), P. 3107 - 3124

Published: Sept. 10, 2021

Recent advances in genome editing technologies have magnified the prospect of single-dose cures for many genetic diseases. For most disorders, precise DNA correction is anticipated to best treat patients. To install desired changes with high precision, our laboratory developed base editors (BEs), which can correct four common single-base substitutions, and prime editors, any substitution, insertion, and/or deletion over a stretch dozens pairs. Compared nuclease-dependent approaches that involve double-strand breaks (DSBs) often result large percentage uncontrolled outcomes, such as mixtures insertions deletions (indels), larger deletions, chromosomal rearrangements, offer greater efficiency fewer byproducts slowly dividing or non-dividing cells, those make up cells adult animals. Both viral non-viral vivo delivery methods now been used deliver animal models, establishing serve effective agents therapeutic This review summarizes examples somatic cell (post-natal) prospects future development.

Language: Английский

Citations

133
Advances in CRISPR therapeutics DOI Open Access

Michael Chavez,

Xinyi Chen,

Paul B. Finn

et al.

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 19(1), P. 9 - 22

Published: Oct. 24, 2022

Language: Английский

Citations

115
Engineering a precise adenine base editor with minimal bystander editing DOI
Liang Chen, Shun Zhang, Niannian Xue

et al.

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 19(1), P. 101 - 110

Published: Oct. 13, 2022

Language: Английский

Citations

105
Genotoxic effects of base and prime editing in human hematopoietic stem cells DOI Creative Commons
Martina Fiumara, Samuele Ferrari, Attya Omer

et al.

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(6), P. 877 - 891

Published: Sept. 7, 2023

Base and prime editors (BEs PEs) may provide more precise genetic engineering than nuclease-based approaches because they bypass the dependence on DNA double-strand breaks. However, little is known about their cellular responses genotoxicity. Here, we compared state-of-the-art BEs PEs Cas9 in human hematopoietic stem progenitor cells with respect to editing efficiency, cytotoxicity, transcriptomic changes on-target genome-wide induced detrimental transcriptional that reduced efficiency repopulation xenotransplants also generated breaks genotoxic byproducts, including deletions translocations, at a lower frequency Cas9. These effects were strongest for cytidine due suboptimal inhibition of base excision repair mitigated by tailoring delivery timing editor expression through optimized mRNA design. altered mutational landscape across genome increasing load relative proportions nucleotide variants. findings raise concerns genotoxicity warrant further investigation view clinical application.

Language: Английский

Citations

96