Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies DOI Creative Commons
Olivier Nolan-Stevaux, Richard Smith

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 13, 2024

CAR-T cell and T engager therapies have demonstrated transformational efficacy against hematological malignancies, but achieving in solid tumors has been more challenging, large part because of on-target/off-tumor toxicities sub-optimal anti-tumor cytotoxic functions. Here, we discuss engineering solutions that exploit biological properties to overcome these challenges. Using logic gates as a framework, categorize the numerous approaches leverage two inputs instead one achieve better cancer selectivity or with dual-input CAR-Ts multi-specific TCEs. In addition “OR gate” “AND dual tumor antigen targeting, also review “contextual AND technologies whereby continuous cancer-selective such pH, hypoxia, target density, proteases, immune-suppressive cytokine gradients can be creatively incorporated therapy designs. We introduce notion “output directionality” distinguish strategies mechanistically impact killing fitness. Finally, contrast feasibility potential benefits various using TCE therapeutics why promising “IF/THEN” “NOT” gate types pertain specifically therapies, succeed by integrating both technologies.

Language: Английский

Robust genome editing activity and the applications of enhanced miniature CRISPR-Cas12f1 DOI Creative Commons
Soo-Ji Park,

Sungjin Ju,

Won Jun Jung

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 15, 2025

Abstract With recent advancements in gene editing technology using the CRISPR/Cas system, there is a demand for more effective editors. A key factor facilitating efficient CRISPR delivery into cells, which known to be associated with size of system. Accordingly, compact CRISPR-Cas systems derived from various strains are discovered, among Un1Cas12f1 2.6 times smaller than SpCas9, providing advantages therapy research. Despite extensive engineering efforts improve Un1Cas12f1, efficiency still shown low depending on target site. To overcome this limitation, we develop enhanced Cas12f1 (eCas12f1), exhibits activity similar SpCas9 and AsCpf1, even targets where previously improved variants showed efficiency. Furthermore, demonstrate that eCas12f1 efficiently induces apoptosis cancer cells compatible base regulation expression, verifying its high utility applicability

Language: Английский

Citations

2
Recent Therapeutic Gene Editing Applications to Genetic Disorders DOI Creative Commons
Éric Deneault

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4147 - 4185

Published: April 30, 2024

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss progression of milestones leading emergence clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications human genome. CRISPR-Cas9 nuclease, base prime editing taken center stage, demonstrating remarkable precision efficacy ex vivo genomic modifications. Enhanced delivery systems, including viral vectors nanoparticles, further improved efficiency safety advancing their clinical translatability. The exploration CRISPR-Cas systems beyond commonly used Cas9, such development Cas12 Cas13 variants, has expanded repertoire tools, enabling more intricate interventions. Outstandingly, represents significant leap forward, given its unparalleled versatility minimization off-target effects. These innovations paved way multitude previously incurable disorders, ranging from monogenic diseases complex polygenic conditions. This review highlights latest innovative studies field, emphasizing breakthrough technologies preclinical trials, applications realm medicine. However, challenges effects ethical considerations remain, necessitating continued research refine profiles frameworks.

Language: Английский

Citations

8
Therapeutic In Vivo Gene Editing Achieved by a Hypercompact CRISPR‐Cas12f1 System Delivered with All‐in‐One Adeno‐Associated Virus DOI Creative Commons

Tongtong Cui,

Bingyu Cai, Yao Tian

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(19)

Published: Feb. 26, 2024

CRISPR-based gene therapies are making remarkable strides toward the clinic. But large size of most widely used Cas endonucleases including Cas9 and Cas12a restricts their efficient delivery by adeno-associated virus (AAV) for in vivo editing. Being exceptionally small, recently engineered type V-F CRISPR-Cas12f1 systems can overcome cargo packaging bottleneck present as strong candidates therapeutic applications. In this study, pairwise editing efficiencies different Cas12f1/sgRNA scaffold combinations systemically screened optimized, CasMINI_v3.1/ge4.1 system is identified being able to significantly boost activity. Moreover, packaged into single AAV vectors delivered via subretinal injection, achieves remarkably high efficiencies, over 70% transduced retinal cells. Further, efficacy Cas12f1 system-based therapy treat retinitis pigmentosa Rho

Language: Английский

Citations

7
From bench to bedside: Developing CRISPR/Cas-based therapy for ocular diseases DOI Creative Commons
Qing Zhao, L. J. Wei, Youxin Chen

et al.

Pharmacological Research, Journal Year: 2025, Volume and Issue: unknown, P. 107638 - 107638

Published: Jan. 1, 2025

Language: Английский

Citations

0
Optogenetics and Targeted Gene Therapy for Retinal Diseases: Unravelling the Fundamentals, Applications, and Future Perspectives DOI Open Access
Merve Kulbay,

Nicolas Tuli,

Arjin Akdag

et al.

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(14), P. 4224 - 4224

Published: July 19, 2024

With a common aim of restoring physiological function defective cells, optogenetics and targeted gene therapies have shown great clinical potential novelty in the branch personalized medicine inherited retinal diseases (IRDs). The basis aims to bypass photoreceptors by introducing opsins with light-sensing capabilities. In contrast, therapies, such as methods based on CRISPR-Cas9 RNA interference noncoding RNAs (i.e., microRNA, small interfering RNA, short hairpin RNA), consists inducing normal or protein expression into affected cells. Having partially leveraged challenges limiting their prompt introduction practice engineering, cell tissue delivery capabilities), it is crucial deepen fields knowledge applied therapy. this in-depth novel literature review explain fundamentals applications while providing decision-making arguments for ophthalmologists. First, we biomolecular principles engineering steps involved mentioned above bringing focus specific vectors molecules signalization. importance vector choice are discussed. Second, summarize ongoing trials most recent discoveries IRDs. Finally, then discuss limits current each We provide first time scientific-based explanations clinicians justify specificity therapy one disease, which can help improve tasks.

Language: Английский

Citations

3
Perspectives on CRISPR Genome Editing to Prevent Prion Diseases in High-Risk Individuals DOI Creative Commons

Milan M. Medd,

Qi Cao

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1725 - 1725

Published: Aug. 1, 2024

Prion diseases are neurodegenerative disorders caused by misfolded prion proteins. Although rare, the said always fatal; they commonly cause death within months of developing clinical symptoms, and their diagnosis is exceptionally difficult pre-mortem. There no known cures or treatments other than symptomatic care. Given aggressiveness on onset, therapies after disease onset could be challenging. Prevention to reduce incidence delay has been suggested a more feasible approach. In this perspective article, we summarize our current understandings origin, risk factors, manifestations diseases. We propose PCR testing blood identify

Language: Английский

Citations

0
Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies DOI Creative Commons
Olivier Nolan-Stevaux, Richard Smith

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 13, 2024

CAR-T cell and T engager therapies have demonstrated transformational efficacy against hematological malignancies, but achieving in solid tumors has been more challenging, large part because of on-target/off-tumor toxicities sub-optimal anti-tumor cytotoxic functions. Here, we discuss engineering solutions that exploit biological properties to overcome these challenges. Using logic gates as a framework, categorize the numerous approaches leverage two inputs instead one achieve better cancer selectivity or with dual-input CAR-Ts multi-specific TCEs. In addition “OR gate” “AND dual tumor antigen targeting, also review “contextual AND technologies whereby continuous cancer-selective such pH, hypoxia, target density, proteases, immune-suppressive cytokine gradients can be creatively incorporated therapy designs. We introduce notion “output directionality” distinguish strategies mechanistically impact killing fitness. Finally, contrast feasibility potential benefits various using TCE therapeutics why promising “IF/THEN” “NOT” gate types pertain specifically therapies, succeed by integrating both technologies.

Language: Английский

Citations

0