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Applications of CRISPR-Cas Technologies to Proteomics.
CRISPR-Cas-based genome editing is a revolutionary approach that has provided an unprecedented investigational power for the life sciences. Rapid and efficient, CRISPR-Cas technologies facilitate the generation of complex biological models and at the same time provide the necessary methods required to study these models in depth. The field of proteomics has already significantly benefited from leveraging the power of CRISPR-Cas technologies, however, many potential applications of these technologies in the context of proteomics remain unexplored. In this review, we intend to provide an introduction to the CRISPR-Cas technologies and demonstrate how they can be applied to solving proteome-centric questions. To achieve this goal, we begin with the description of the modern suite of CRISPR-Cas-based tools, focusing on the more mature CRISPR-Cas9 system. In the second part of this review, we highlight both established and potential applications of the CRISPR-Cas technologies to proteomics.
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Spacer-Complementary Single-Stranded DNA Oligonucleotides Can Serve as Target-Specific Inhibitors in CRISPR/Cas9 Systems.
The continuous expression of the CRISPR/Cas system in organisms can lead to various potential issues. Some anti-CRISPR strategies have been developed to achieve precise control over CRISPR/Cas, yet these strategies are predominantly protein-based, with the most commonly used anti-CRISPR (Acr) proteins lacking sufficient target specificity. However, in this study, we designed a single-stranded DNA (ssDNA) inhibitor that was complementary to the spacer region on the guide RNA, operating at the nucleic acid level. We demonstrated that this method effectively inhibits the cleavage activity of Cas9-sgRNA ribonucleoprotein (RNP) in a target-specific manner through in vitro cleavage experiments. Furthermore, we explored the binding position and effective length of this inhibitory ssDNA, finding that its inhibitory effect was significantly reduced when the length of continuous complementarity with the 5' end of the spacer was less than 7nt. The truncated ssDNA also showed potential in reducing off-target effects. Moreover, we applied nucleic acid inhibitors to embryos via microinjection, and gene editing activity was significantly reduced, as evidenced by a decrease in the mosaicism rate of mouse embryos undergoing normal gene editing from (84.4 ± 4.4) % to 0%. Our study introduces a convenient and target-specific nucleic acid inhibitor capable of achieving precise regulation of gene editing.
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Generation of a heterozygous COL2A1 (p.R989C) spondyloepiphyseal dysplasia congenita mutation iPSC line, MCRIi001-B, using CRISPR/Cas9 gene editing.
To produce an in vitro model of the human chondrodysplasia, spondyloepiphyseal dysplasia congenita, we used CRISPR/Cas9 gene editing to generate a heterozygous patient COL2A1 mutation in an established control human iPSC line. The gene-edited heterozygous COL2A1 p.R989C line had a normal karyotype, expressed pluripotency markers, and could differentiate into cells representative of the three embryonic germ layers. When differentiated into cartilage this cell line and the parental isogenic control may be used to explore disease mechanisms and evaluate therapeutic approaches.
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Epigenome editing for herbicide-resistant crops.
Herbicide resistance (HR) is fundamental for sustainable agriculture as global food security increasingly relies on efficient and eco-friendly weed management. Recent advances in CRISPR/dCas9-based epigenome editing offer a promising, non-genetic approach by precisely targeting regulatory regions of genes involved in herbicide sensitivity and detoxification. While CRISPR/Cas9 has successfully been used to develop HR crops, CRISPR/dCas9 remains underexplored in this field. We propose that CRISPR/dCas9-driven epigenome editing could enable time- and tissue-specific control of gene expression, allowing for the introduction of heritable HR traits without altering DNA sequences. This innovative approach could transform sustainable HR development, offering a powerful solution to enhance agricultural resilience and food security while aligning with eco-friendly weed management strategies.
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Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer.
The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) gene editing has attracted extensive attentions in various fields, however, its clinical application is hindered by the lack of effective and safe delivery system. Herein, we reported a cationic micelle nanoparticle composed of cholesterol-modified branched small molecular PEI (PEI-CHO) and biodegradable PEG-b-polycarbonate block copolymer (PEG-PC), denoted as PEG-PC/PEI-CHO/pCas9, for the CRISPR/Cas9 delivery to realize genomic editing in cancer. Specifically, PEI-CHO condensed pCas9 into nanocomplexes, which were further encapsulated into PEG-PC nanoparticles (PEG-PC/PEI-CHO/pCas9). PEG-PC/PEI-CHO/pCas9 had a PEG shell, protecting DNA from degradation by nucleases. Enhanced cellular uptake of PEG-PC/PEI-CHO/pCas9 nanoparticles was observed as compared to that mediated by Lipo2k/pCas9 nanoparticles, thus leading to significantly elevated transfection efficiency after escaping from endosomes via the proton sponge effect of PEI. In addition, the presence of PEG shell greatly improved biocompatibility, and significantly enhanced the in vivo tumor retention of pCas9 compared to PEI-CHO/pCas9. Notably, apparent downregulation of GFP expression could be achieved both in vitro and in vivo by using PEG-PC/PEI-CHO/pCas9-sgGFP nanoparticles. Furthermore, PEG-PC/PEI-CHO/pCas9-sgMcl1 induced effective apoptosis and tumor suppression in a HeLa tumor xenograft mouse model by downregulating Mcl1 expression. This work may provide an alternative paradigm for the efficient and safe genome editing in cancer.
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Transfecting tissue models with CRISPR/Cas9 plasmid DNA using peptide dendrimers.
There is currently a lack of efficient reagents to transfect cells with large plasmid DNA, which would be enabling tools for gene editing using CRISPR/Cas9 technology. Herein, we report the discovery of peptide dendrimer Z22 as a non-viral vector for transfecting large CRISPR/Cas9 pDNA into 3D-tumor spheroids with exceptionally high efficiency, low cytotoxicity and low immunogenicity.
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Small nucleic acids and the path to the clinic for anti-CRISPR.
CRISPR-based therapeutics have entered clinical trials but no methods to inhibit Cas enzymes have been demonstrated in a clinical setting. The ability to inhibit CRISPR-based gene editing or gene targeting drugs should be considered a critical step in establishing safety standards for many CRISPR-Cas therapeutics. Inhibitors can act as a failsafe or as an adjuvant to reduce off-target effects in patients. In this review we discuss the need for clinical inhibition of CRISPR-Cas systems and three existing inhibitor technologies: anti-CRISPR (Acr) proteins, small molecule Cas inhibitors, and small nucleic acid-based CRISPR inhibitors, CRISPR SNuBs. Due to their unique properties and the recent successes of other nucleic acid-based therapeutics, CRISPR SNuBs appear poised for clinical application in the near-term.
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An update on Alzheimer's disease: Immunotherapeutic agents, stem cell therapy and gene editing.
Alzheimer's disease is a chronic lifestyle ailment whose occurrence has come to light with the increasing life expectancy due to better healthcare. The patient burden for AD is set to double by the year 2060 and advancement in research is of utmost importance to combat this problem. AD is characterized by the pathological hallmarks of amyloid plaques and neurofibrillary tangles. The disease has been implicated to have a genetic predisposition. The current treatment strategies are at best ameliorative in nature and offer no substantive cure. Immunotherapeutic approaches employed have shown few therapeutic benefits but the accelerated approval of aducanumab by the US-FDA shows clinical benefit merit. In addition, newer therapeutic approaches are the need of the hour. This review aims to highlight the pathology of the disease, followed by an insight into newer approaches like stem cell therapy and gene editing, focusing on possible CRISPR mediated targets.
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Current Landscape of Various Techniques and Methods of Gene Therapy through CRISPR Cas9 along with its Pharmacological and Interventional Therapies in the Treatment of Type 2 Diabetes Mellitus.
BACKGROUND: Type 2 diabetes mellitus (T2DM) is frequently referred to as a "lifestyle illness". In 2000, India (31.7 million) had the greatest global prevalence of diabetes mellitus, followed by China (20.8 million), the United States (17.7 million), and other countries. In recent years, the treatment of gene therapy (T2DM) has attracted intensive interest. OBJECTIVE: We aimed to critically review the literature on the various techniques and methods, which may be a possible novel approach through the gene therapy CRISPR Cas9 and some other gene editing techniques for T2DM. Interventional and pharmacological approaches for the treatment of T2DM were also included to identify novel therapies for its treatment. METHOD: An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer. CONCLUSION: It can be concluded from the study that recent advancements in gene-editing technologies, such as CRISPR Cas9, have opened new avenues for the development of novel therapeutic approaches for T2DM. CRISPR Cas9 is a powerful tool that enables precise and targeted modifications of the genome.
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CCR5 gene editing and HIV immunotherapy: current understandings, challenges, and future directions.
Human immunodeficiency virus (HIV) infection remains a major global public health challenge. Although highly active antiretroviral therapy (HAART or ART) can effectively control viral replication, it fails to eradicate latent viral reservoirs and poses limitations such as lifelong medication and cumulative drug toxicity. This study focuses on the pivotal role of C-C chemokine receptor 5 (CCR5) gene editing in HIV immunotherapy, particularly highlighting the natural resistance to R5-tropic HIV strains observed in the "Berlin" and "London" patients carrying the homozygous CCR5-Δ32 mutation. We further explore the synergistic potential of multiplex gene editing strategies-including CCR5, CXCR4, and HIV LTR loci-and the combinatorial mechanisms between gene editing technologies and immunotherapy. A personalized treatment framework is proposed to address the clinical heterogeneity among people living with HIV. In addition, we assess the balance between long-term safety and global accessibility of gene-editing approaches such as CRISPR/Cas9, emphasizing strategies to enhance therapeutic efficacy while reducing cost and off-target effects. Our findings suggest that the integration of CCR5-targeted gene editing with immune-based interventions holds great promise for overcoming current therapeutic limitations and achieving functional HIV cure. However, key challenges-such as immune rejection, viral tropism switching, and economic feasibility-must be resolved. This integrative approach provides a robust theoretical and technical foundation for the next generation of HIV treatment paradigms.
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