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1
Chung, Sun-Ku, and Seo-Young Lee. "Advances in Gene Therapy Techniques to Treat LRRK2 Gene Mutation." Biomolecules 12, no. 12 (December 5, 2022): 1814. http://dx.doi.org/10.3390/biom12121814.
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Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases (ZFNs), helper-dependent adenoviral vector (HDAdV), the bacterial artificial chromosome-based homologous recombination (BAC-based HR) system, and CRISPR/Cas9-homology-directed repair (HDR) or adenine base editor (ABE) are used in genome editing. Gene correction of the LRRK2 G2019S mutation has been applied whenever new gene therapy tools emerge, being mainly applied to induced pluripotent stem cells (LRRK2 G2019S-mutant iPSCs). Here, we comprehensively introduce the principles and methods of each programmable nuclease such as ZFN, CRISPR/Cas9-HDR or ABE applied to LRRK2 G2019S, as well as those of HDAdV or BAC-based HR systems used as nonprogrammable nuclease systems.
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Rahman, Mujeeb ur, Muhammad Bilal, Junaid Ali Shah, Ajeet Kaushik, Pierre-Louis Teissedre, and Małgorzata Kujawska. "CRISPR-Cas9-Based Technology and Its Relevance to Gene Editing in Parkinson’s Disease." Pharmaceutics 14, no. 6 (June 13, 2022): 1252. http://dx.doi.org/10.3390/pharmaceutics14061252.
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Parkinson’s disease (PD) and other chronic and debilitating neurodegenerative diseases (NDs) impose a substantial medical, emotional, and financial burden on individuals and society. The origin of PD is unknown due to a complex combination of hereditary and environmental risk factors. However, over the last several decades, a significant amount of available data from clinical and experimental studies has implicated neuroinflammation, oxidative stress, dysregulated protein degradation, and mitochondrial dysfunction as the primary causes of PD neurodegeneration. The new gene-editing techniques hold great promise for research and therapy of NDs, such as PD, for which there are currently no effective disease-modifying treatments. As a result, gene therapy may offer new treatment options, transforming our ability to treat this disease. We present a detailed overview of novel gene-editing delivery vehicles, which is essential for their successful implementation in both cutting-edge research and prospective therapeutics. Moreover, we review the most recent advancements in CRISPR-based applications and gene therapies for a better understanding of treating PD. We explore the benefits and drawbacks of using them for a range of gene-editing applications in the brain, emphasizing some fascinating possibilities.
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De Plano, Laura M., Giovanna Calabrese, Sabrina Conoci, Salvatore P. P. Guglielmino, Salvatore Oddo, and Antonella Caccamo. "Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders." International Journal of Molecular Sciences 23, no. 15 (August 5, 2022): 8714. http://dx.doi.org/10.3390/ijms23158714.
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Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.
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Katzmann, Julius L., Arjen J. Cupido, and Ulrich Laufs. "Gene Therapy Targeting PCSK9." Metabolites 12, no. 1 (January 12, 2022): 70. http://dx.doi.org/10.3390/metabo12010070.
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The last decades of research in cardiovascular prevention have been characterized by successful bench-to-bedside developments for the treatment of low-density lipoprotein (LDL) hypercholesterolemia. Recent examples include the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies, small interfering RNA and antisense RNA drugs. The cumulative effects of LDL cholesterol on atherosclerosis make early, potent, and long-term reductions in LDL cholesterol desirable—ideally without the need of regular intake or application of medication and importantly, without side effects. Current reports show durable LDL cholesterol reductions in primates following one single treatment with PCSK9 gene or base editors. Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes. Provided safety and documentation of a reduction in cardiovascular events, this novel technique has the potential to fundamentally change our current concepts of cardiovascular prevention. In this review, the application of the CRISPR/Cas system is explained and the current state of in vivo approaches of PCSK9 editing is presented.
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Tang, Xuanting. "CRISPR/Cas9-based genome engineering in HIV gene therapy." E3S Web of Conferences 233 (2021): 02004. http://dx.doi.org/10.1051/e3sconf/202123302004.
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In recent years, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) technology has become the most heated genome editing technique. Comparing to earlier genetic engineering methods, the CRISPR/Cas system is more advantageous due to its simple convenient design, high efficiency, cost-effectiveness, and the ability to perform multi-sites editing simultaneously. As the most effective gene editing tool, it utilizes a simple short RNA-guided mechanism to direct Cas-mediated DNA cleavage at the target genome locus and exploits the endogenous DNA repair pathways to achieve site-specific gene modifications. Initially discovered as a part of the bacterial adaptive immune system, the CRISPR/Cas system has now been widely used to study a broad range of biological genomes. Besides its contribution to our understanding of the basic genetic science, the application of the CRISPR/Cas system also expands rapidly into the medical fields, showing great potentials in the research of genetic diseases, viral infectious diseases, and cancers. In this review, the latest research progress of CRISPR/Cas technology is summarized based on its development, mechanism, and application in HIV/AIDS intervention. This review also examines the existing weaknesses and the future prospects of this promising technology.
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S., Manasa M. "CRISPR-Cas9 gene editing technology in human gene therapy: the new realm of medicine." International Journal of Advances in Medicine 9, no. 4 (March 24, 2022): 513. http://dx.doi.org/10.18203/2349-3933.ijam20220796.
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Gene therapy has a huge clinical relevance in the present therapeutic world and is one of the many research fields of biology which received many benefits from the recent advancements of modern clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing technology. Researchers are on the way to make significant changes in the ways of treating genetic abnormalities. An increase in the number of approved clinical trials of CRISPR based gene therapy shows we are not too far from eliminating deadly diseases such as acquired immunodeficiency syndrome (AIDS), cancer and many inherited genetic conditions from the society. However, there are some challenges associated with the development of CRISPR technology in medical field most of which revolves around its safety, efficiency and ethics. Lack of an optimized method by which the CRISPR-Cas9 expression cassette can be delivered to cells is one of the main challenges when it comes to its application in human gene therapy. Although viral vectors are the most common delivery systems used in gene therapy, recent researches show promising results on using lipid- based l delivery systems such as liposome-templated hydrogel nanoparticles (LHNPs). As these could eliminate the safety concerns of using viral vectors, it is expected to have potential therapeutic applications in future. Nevertheless, the efficiency of non-viral systems is still not fully comparable with that of viral vectors. Hence, CRISPR based therapies might take longer than expected to be prevalent in the medical field. In this short review, the recent advances of CRISPR technology in gene therapy is discussed along with its challenges and limitations.
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Preece, Roland, and Christos Georgiadis. "Emerging CRISPR/Cas9 applications for T-cell gene editing." Emerging Topics in Life Sciences 3, no. 3 (April 2, 2019): 261–75. http://dx.doi.org/10.1042/etls20180144.
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Abstract Gene editing tools are being rapidly developed, accelerating many areas of cell and gene therapy research. Each successive gene editing technology promises increased efficacy, improved specificity, reduced manufacturing cost and design complexity; all of which are currently epitomised by the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein (Cas9) platform. Since its conceptualisation, CRISPR-based gene editing has been applied to existing methodologies and has further allowed the exploration of novel avenues of research. Implementation of CRISPR/Cas9 has been instrumental to recent progress in the treatment of cancer, primary immunodeficiency, and infectious diseases. To this end, T-cell therapies have attempted to harness and redirect antigen recognition function, and through gene editing, broaden T-cell targeting capabilities and enhance their potency. The purpose of this review is to provide insights into emerging applications of CRISPR/Cas9 in T-cell therapies, to briefly address concerns surrounding CRISPR-mediated indel formation, and to introduce CRISPR/Cas9 base editing technologies that hold vast potential for future research and clinical translation.
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Liu, Wenlou, Chunsheng Yang, Yanqun Liu, and Guan Jiang. "CRISPR/Cas9 System and its Research Progress in Gene Therapy." Anti-Cancer Agents in Medicinal Chemistry 19, no. 16 (January 23, 2020): 1912–19. http://dx.doi.org/10.2174/1871520619666191014103711.
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Genome editing refers to changing the genome sequence of an organism by knockout, insertion, and site mutation, resulting in changes in the genetic information of the organism. The clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein-9 nuclease (Cas9) system is a genome editing technique developed by the acquired immune system in the microbes, such as bacteria and archaebacteria, which targets and edits genome sequences according to the principle of complementary base pairing. This technique can be used to edit endogenous genomic DNA sequences in organisms accurately and has been widely used in fields, such as biotechnology, cancer gene therapy, and dermatology. In this review, we summarize the history, structure, mechanism, and application of CRISPR/Cas9 in gene therapy and dermatological diseases.
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Salsman, Jayme, and Graham Dellaire. "Precision genome editing in the CRISPR era." Biochemistry and Cell Biology 95, no. 2 (April 2017): 187–201. http://dx.doi.org/10.1139/bcb-2016-0137.
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With the introduction of precision genome editing using CRISPR–Cas9 technology, we have entered a new era of genetic engineering and gene therapy. With RNA-guided endonucleases, such as Cas9, it is possible to engineer DNA double strand breaks (DSB) at specific genomic loci. DSB repair by the error-prone non-homologous end-joining (NHEJ) pathway can disrupt a target gene by generating insertions and deletions. Alternatively, Cas9-mediated DSBs can be repaired by homology-directed repair (HDR) using an homologous DNA repair template, thus allowing precise gene editing by incorporating genetic changes into the repair template. HDR can introduce gene sequences for protein epitope tags, delete genes, make point mutations, or alter enhancer and promoter activities. In anticipation of adapting this technology for gene therapy in human somatic cells, much focus has been placed on increasing the fidelity of CRISPR–Cas9 and increasing HDR efficiency to improve precision genome editing. In this review, we will discuss applications of CRISPR technology for gene inactivation and genome editing with a focus on approaches to enhancing CRISPR–Cas9-mediated HDR for the generation of cell and animal models, and conclude with a discussion of recent advances and challenges towards the application of this technology for gene therapy in humans.
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Kanu, Gayathri A., Javad B. M. Parambath, Raed O. Abu Odeh, and Ahmed A. Mohamed. "Gold Nanoparticle-Mediated Gene Therapy." Cancers 14, no. 21 (October 31, 2022): 5366. http://dx.doi.org/10.3390/cancers14215366.
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Gold nanoparticles (AuNPs) have gained increasing attention as novel drug-delivery nanostructures for the treatment of cancers, infections, inflammations, and other diseases and disorders. They are versatile in design, synthesis, modification, and functionalization. This has many advantages in terms of gene editing and gene silencing, and their application in genetic illnesses. The development of several techniques such as CRISPR/Cas9, TALEN, and ZFNs has raised hopes for the treatment of genetic abnormalities, although more focused experimentation is still needed. AuNPs, however, have been much more effective in trending research on this subject. In this review, we highlight recently well-developed advancements that are relevant to cutting-edge gene therapies, namely gene editing and gene silencing in diseases caused by a single gene in humans by taking an edge of the unique properties of the AuNPs, which will be an important outlook for future research.
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Khan, Sikandar Hayat. "Type-2 Diabetes and Gene Therapy: The Promise of CRISPR Gene Therapy in type-2 Diabetes Mellitus." Journal Of Obesity Management 1, no. 3 (September 23, 2019): 1–5. http://dx.doi.org/10.14302/issn.2574-450x.jom-19-3001.
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Gene therapy has entered a new era with the dawn of CRISPR/Cas9 technology which though were always available in nature but rediscovered to tame into a real-tlife genome editing tool. With the modernization upsurge and changes in ways the “homo sapiens” survived on this planet from hunger to current era of exuberance has led to multiple metabolic issues like type-2 diabetes. Notwithstanding the rapid emergence of medication to suppress the hyperglycemia and insulin resistance associated with this menace, need has definitely emerge to find more personalized and curative dimensions to therapeutics of type-2 diabetes mellitus. Gene therapy is one more addition to Type-2 Diabetes Mellitus (T2DM) therapy, where multiple options have emerged in the shape of microRNA, direct knocking out of cellular structures like proteins and enzymes and very recently the precision nucleases associated with CRISPR technologies. This mini-review attempt to summarize some of the recent examples of gene therapy with major focus on CRISPR/Cas technologies.
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Naso, Gaetano, and Anastasia Petrova. "CRISPR/Cas9 gene editing for genodermatoses: progress and perspectives." Emerging Topics in Life Sciences 3, no. 3 (April 5, 2019): 313–26. http://dx.doi.org/10.1042/etls20180148.
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Abstract Genodermatoses constitute a clinically heterogeneous group of devastating genetic skin disorders. Currently, therapy options are largely limited to symptomatic treatments and although significant advances have been made in ex vivo gene therapy strategies, various limitations remain. However, the recent technical transformation of the genome editing field promises to overcome the hurdles associated with conventional gene addition approaches. In this review, we discuss the need for developing novel treatments and describe the current status of gene editing for genodermatoses, focusing on a severe blistering disease called epidermolysis bullosa (EB), for which significant progress has been made. Initial research utilized engineered nucleases such as transcription activator-like effector nucleases and meganucleases. However, over the last few years, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) have upstaged older generation gene editing tools. We examine different strategies for CRISPR/Cas9 application that can be employed depending on the type and position of the mutation as well as the mode of its inheritance. Promising developments in the field of base editing opens new avenues for precise correction of single base substitutions, common in EB and other genodermatoses. We also address the potential limitations and challenges such as safety concerns and delivery efficiency. This review gives an insight into the future of gene editing technologies for genodermatoses.
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Koniali, Lola, Carsten W. Lederer, and Marina Kleanthous. "Therapy Development by Genome Editing of Hematopoietic Stem Cells." Cells 10, no. 6 (June 14, 2021): 1492. http://dx.doi.org/10.3390/cells10061492.
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Accessibility of hematopoietic stem cells (HSCs) for the manipulation and repopulation of the blood and immune systems has placed them at the forefront of cell and gene therapy development. Recent advances in genome-editing tools, in particular for clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) and CRISPR/Cas-derived editing systems, have transformed the gene therapy landscape. Their versatility and the ability to edit genomic sequences and facilitate gene disruption, correction or insertion, have broadened the spectrum of potential gene therapy targets and accelerated the development of potential curative therapies for many rare diseases treatable by transplantation or modification of HSCs. Ongoing developments seek to address efficiency and precision of HSC modification, tolerability of treatment and the distribution and affordability of corresponding therapies. Here, we give an overview of recent progress in the field of HSC genome editing as treatment for inherited disorders and summarize the most significant findings from corresponding preclinical and clinical studies. With emphasis on HSC-based therapies, we also discuss technical hurdles that need to be overcome en route to clinical translation of genome editing and indicate advances that may facilitate routine application beyond the most common disorders.
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Bonillo, Mario, Julia Pfromm, and M. Dominik Fischer. "Challenges to Gene Editing Approaches in the Retina." Klinische Monatsblätter für Augenheilkunde 239, no. 03 (March 2022): 275–83. http://dx.doi.org/10.1055/a-1757-9810.
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AbstractRetinal gene therapy has recently been at the cutting edge of clinical development in the diverse field of genetic therapies. The retina is an attractive target for genetic therapies such as gene editing due to the distinctive anatomical and immunological features of the eye, known as immune privilege, so that inherited retinal diseases (IRDs) have been studied in several clinical studies. Thus, rapid strides are being made toward developing targeted treatments for IRDs. Gene editing in the retina faces a group of heterogenous challenges, including editing efficiencies, off-target effects, the anatomy of the target organ, immune responses, inactivation, and identifying optimal application methods. As clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) based technologies are at the forefront of current gene editing advances, their specific editing efficiency challenges and potential off-target effects were assessed. The immune privilege of the eye reduces the likelihood of systemic immune responses following retinal gene therapy, but possible immune responses must not be discounted. Immune responses to gene editing in the retina may be humoral or cell mediated, with immunologically active cells, including microglia, implicated in facilitating possible immune responses to gene editing. Immunogenicity of gene therapeutics may also lead to the inactivation of edited cells, reducing potential therapeutic benefits. This review outlines the broad spectrum of potential challenges currently facing retinal gene editing, with the goal of facilitating further advances in the safety and efficacy of gene editing therapies.
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Rosenblum, Daniel, Anna Gutkin, Ranit Kedmi, Srinivas Ramishetti, Nuphar Veiga, Ashley M. Jacobi, Mollie S. Schubert, et al. "CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy." Science Advances 6, no. 47 (November 2020): eabc9450. http://dx.doi.org/10.1126/sciadv.abc9450.
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Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid. A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.
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García-Fernández, Alba, Gema Vivo-Llorca, Mónica Sancho, Alicia Belén García-Jareño, Laura Ramírez-Jiménez, Eloísa Barber-Cano, José Ramón Murguía, Mar Orzáez, Félix Sancenón, and Ramón Martínez-Máñez. "Nanodevices for the Efficient Codelivery of CRISPR-Cas9 Editing Machinery and an Entrapped Cargo: A Proposal for Dual Anti-Inflammatory Therapy." Pharmaceutics 14, no. 7 (July 19, 2022): 1495. http://dx.doi.org/10.3390/pharmaceutics14071495.
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In this article, we report one of the few examples of nanoparticles capable of simultaneously delivering CRISPR-Cas9 gene-editing machinery and releasing drugs for one-shot treatments. Considering the complexity of inflammation in diseases, the synergistic effect of nanoparticles for gene-editing/drug therapy is evaluated in an in vitro inflammatory model as proof of concept. Mesoporous silica nanoparticles (MSNs), able to deliver the CRISPR/Cas9 machinery to edit gasdermin D (GSDMD), a key protein involved in inflammatory cell death, and the anti-inflammatory drug VX-765 (GSDMD45CRISPR-VX-MSNs), were prepared. Nanoparticles allow high cargo loading and CRISPR-Cas9 plasmid protection and, thus, achieve the controlled codelivery of CRISPR-Cas9 and the drug in cells. Nanoparticles exhibit GSDMD gene editing by downregulating inflammatory cell death and achieving a combined effect on decreasing the inflammatory response by the codelivery of VX-765. Taken together, our results show the potential of MSNs as a versatile platform by allowing multiple combinations for gene editing and drug therapy to prepare advanced nanodevices to meet possible biomedical needs.
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Fang, Ton, Goun Je, Peter Pacut, Kiandokht Keyhanian, Jeff Gao, and Mehdi Ghasemi. "Gene Therapy in Amyotrophic Lateral Sclerosis." Cells 11, no. 13 (June 29, 2022): 2066. http://dx.doi.org/10.3390/cells11132066.
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Since the discovery of Cu/Zn superoxide dismutase (SOD1) gene mutation, in 1993, as the first genetic abnormality in amyotrophic lateral sclerosis (ALS), over 50 genes have been identified as either cause or modifier in ALS and ALS/frontotemporal dementia (FTD) spectrum disease. Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. During the last three decades, tremendous effort has been made worldwide to reveal biological pathways underlying the pathogenesis of these gene mutations in ALS/FTD. Accordingly, targeting etiologic genes (i.e., gene therapies) to suppress their toxic effects have been investigated widely. It includes four major strategies: (i) removal or inhibition of abnormal transcribed RNA using microRNA or antisense oligonucleotides (ASOs), (ii) degradation of abnormal mRNA using RNA interference (RNAi), (iii) decrease or inhibition of mutant proteins (e.g., using antibodies against misfolded proteins), and (iv) DNA genome editing with methods such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas). The promising results of these studies have led to the application of some of these strategies into ALS clinical trials, especially for C9orf72 and SOD1. In this paper, we will overview advances in gene therapy in ALS/FTD, focusing on C9orf72, SOD1, TARDBP, and FUS genes.
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Ren, Duohao, Sylvain Fisson, Deniz Dalkara, and Divya Ail. "Immune Responses to Gene Editing by Viral and Non-Viral Delivery Vectors Used in Retinal Gene Therapy." Pharmaceutics 14, no. 9 (September 19, 2022): 1973. http://dx.doi.org/10.3390/pharmaceutics14091973.
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Inherited retinal diseases (IRDs) are a leading cause of blindness in industrialized countries, and gene therapy is quickly becoming a viable option to treat this group of diseases. Gene replacement using a viral vector has been successfully applied and advanced to commercial use for a rare group of diseases. This, and the advances in gene editing, are paving the way for the emergence of a new generation of therapies that use CRISPR–Cas9 to edit mutated genes in situ. These CRISPR-based agents can be delivered to the retina as transgenes in a viral vector, unpackaged transgenes or as proteins or messenger RNA using non-viral vectors. Although the eye is considered to be an immune-privileged organ, studies in animals, as well as evidence from clinics, have concluded that ocular gene therapies elicit an immune response that can under certain circumstances result in inflammation. In this review, we evaluate studies that have reported on pre-existing immunity, and discuss both innate and adaptive immune responses with a specific focus on immune responses to gene editing, both with non-viral and viral delivery in the ocular space. Lastly, we discuss approaches to prevent and manage the immune responses to ensure safe and efficient gene editing in the retina.
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Psatha, Nikoletta, Kiriaki Paschoudi, Anastasia Papadopoulou, and Evangelia Yannaki. "In Vivo Hematopoietic Stem Cell Genome Editing: Perspectives and Limitations." Genes 13, no. 12 (November 27, 2022): 2222. http://dx.doi.org/10.3390/genes13122222.
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The tremendous evolution of genome-editing tools in the last two decades has provided innovative and effective approaches for gene therapy of congenital and acquired diseases. Zinc-finger nucleases (ZFNs), transcription activator- like effector nucleases (TALENs) and CRISPR-Cas9 have been already applied by ex vivo hematopoietic stem cell (HSC) gene therapy in genetic diseases (i.e., Hemoglobinopathies, Fanconi anemia and hereditary Immunodeficiencies) as well as infectious diseases (i.e., HIV), and the recent development of CRISPR-Cas9-based systems using base and prime editors as well as epigenome editors has provided safer tools for gene therapy. The ex vivo approach for gene addition or editing of HSCs, however, is complex, invasive, technically challenging, costly and not free of toxicity. In vivo gene addition or editing promise to transform gene therapy from a highly sophisticated strategy to a “user-friendly’ approach to eventually become a broadly available, highly accessible and potentially affordable treatment modality. In the present review article, based on the lessons gained by more than 3 decades of ex vivo HSC gene therapy, we discuss the concept, the tools, the progress made and the challenges to clinical translation of in vivo HSC gene editing.
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Kesavan, Gokul. "Emerging Gene Editing Therapies for Blood Disorders." Biotechnology Kiosk 3, no. 7 (July 30, 2021): 3–16. http://dx.doi.org/10.37756/bk.21.3.7.1.
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Hemoglobinopathies like sickle cell disease (SCD) and beta thalassemia are the most common monogenic disorders and the number of children born every year with such conditions is predicted to reach about 400,000 by the year 2050. Transplantation of hematopoietic stem cells remains the gold standard of treatment but finding a Human Leukocyte Antigen (HLA)-matched donor is a major bottle neck when large numbers of patients need to be treated. Recent advances in gene editing tools, like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), show immense potential to transform the gene/cell therapy scenario. This review covers recent breakthroughs in treating SCD and transfusion-dependent beta thalassemia such as re-initiation of fetal hemoglobin expression, and the planned clinical trials to correct the sickle cell mutation through CRISPR-based gene repair strategies. Further, expression of Factor IX to treat hemophilia using zinc finger nucleases, and universal Chimeric Antigen Receptor T cells (CAR-T) to treat cancers using genome editing are also discussed. Finally, challenges in developing these gene editing tools for clinical translation along with ensuring their safety, feasibility, and affordability, are also addressed.
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Sun, Jinyu, Jianchu Wang, Donghui Zheng, and Xiaorong Hu. "Advances in therapeutic application of CRISPR-Cas9." Briefings in Functional Genomics 19, no. 3 (November 26, 2019): 164–74. http://dx.doi.org/10.1093/bfgp/elz031.
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Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) is one of the most versatile and efficient gene editing technologies, which is derived from adaptive immune strategies for bacteria and archaea. With the remarkable development of programmable nuclease-based genome engineering these years, CRISPR-Cas9 system has developed quickly in recent 5 years and has been widely applied in countless areas, including genome editing, gene function investigation and gene therapy both in vitro and in vivo. In this paper, we briefly introduce the mechanisms of CRISPR-Cas9 tool in genome editing. More importantly, we review the recent therapeutic application of CRISPR-Cas9 in various diseases, including hematologic diseases, infectious diseases and malignant tumor. Finally, we discuss the current challenges and consider thoughtfully what advances are required in order to further develop the therapeutic application of CRISPR-Cas9 in the future.
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Zhao, Lan, Jian Huang, Yunshan Fan, Jun Li, Tianming You, Shisheng He, Guozhi Xiao, and Di Chen. "Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis." Annals of the Rheumatic Diseases 78, no. 5 (March 6, 2019): 676–82. http://dx.doi.org/10.1136/annrheumdis-2018-214724.
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ObjectivesOsteoarthritis (OA) is a painful and debilitating disease and it is associated with aberrant upregulation of multiple factors, including matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β) and nerve growth factor (NGF). In this study, we aimed to use the CRISPR/Cas9 technology, a highly efficient gene-editing tool, to study whether the ablation of OA-associated genes has OA-modifying effects.MethodsWe performed intra-articular injection of adeno-associated virus, which expressed CRISPR/Cas9 components to target each of the genes encoding MMP13, IL-1β and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1β.ResultsLoss-of-function of NGF palliates pain but worsens joint damage in the surgically induced OA model. Ablation of MMP13 or IL-1β reduces the expression of cartilage-degrading enzymes and attenuates structural deterioration. Targeting both MMP13 and IL-1β significantly mitigates the adverse effects of NGF blockade on the joints.ConclusionsCRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1β or IL-1β attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1β provide benefits on both pain management and joint structure maintenance. Our results suggest that CRISPR-based gene editing is useful for the identification of promising drug targets and the development of feasible therapeutic strategies for OA treatment.
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Kochergin-Nikitsky, K. S., E. V. Zaklyazminskaya, A. V. Lavrov, and S. A. Smirnikhina. "Cardiomyopathies associated with the DES gene mutations: molecular pathogenesis and gene therapy approaches." Almanac of Clinical Medicine 47, no. 7 (December 22, 2019): 603–13. http://dx.doi.org/10.18786/2072-0505-2019-47-025.
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Cardiomyopathy (CMP) is a common group of cardiovascular disorders. Genetic (primary) cardiomyopathies are related to abnormalities in more than 100 genes, including the DES gene encoding desmin protein. Desmin is an essential member of the intermediate filaments, ensuring the structural and functional integrity of myocytes. Mutations in the DES gene result in desmin-related cardiomyopathy with progressive course and poor prognosis. By now, specific therapy for cardiomyopathy has not been developed. Existing conservative and surgical treatment modalities target the rate of heart failure progression and sudden cardiac death prevention but have limited efficacy. The development of gene therapy and genome editing could allow for creating effective and specific methods of gene-based therapy for desminopathies. A number of studies have been published on the use of gene therapy for various genetic cardiomyopathies including those caused by the DES gene mutations, while genome editing has not been used yet. However, promising results have been obtained with CRISPR/Cas9 and TALEN editing systems to correct for “gain-of-function mutations” in some other genes, such as MYBPC3 and PLN. There is also evidence of the possibility to reduce the symptoms of desmin-related cardiomyopathy up to the normal function by knocking out the mutant DES allele, and preserved protein function provided by expression of the normal allele. We believe that genome editing approaches have an open perspective into the development of specific and effective methods to treat desminopathies.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "Genome Editing with Crispr-Cas9 Systems: Basic Research and Clinical Applications." Indonesian Biomedical Journal 9, no. 1 (April 1, 2017): 1. http://dx.doi.org/10.18585/inabj.v9i1.272.
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BACKGROUND: Recently established genome editing technologies will open new avenues for biological research and development. Human genome editing is a powerful tool which offers great scientific and therapeutic potential.CONTENT: Genome editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPRassociated protein 9 (Cas9) technology is revolutionizing the gene function studies and possibly will give rise to an entirely new degree of therapeutics for a large range of diseases. Prompt advances in the CRISPR/Cas9 technology, as well as delivery modalities for gene therapy applications, are dismissing the barriers to the clinical translation of this technology. Many studies conducted showed promising results, but as current available technologies for evaluating off-target gene modification, several elements must be addressed to validate the safety of the CRISPR/Cas9 platform for clinical application, as the ethical implication as well.SUMMARY: The CRISPR/Cas9 system is a powerful genome editing technology with the potential to create a variety of novel therapeutics for a range of diseases, many of which are currently untreatable.KEYWORDS: genome editing, CRISPR-Cas, guideRNA, DSB, ZFNs, TALEN
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Teng, Man, Yongxiu Yao, Venugopal Nair, and Jun Luo. "Latest Advances of Virology Research Using CRISPR/Cas9-Based Gene-Editing Technology and Its Application to Vaccine Development." Viruses 13, no. 5 (April 28, 2021): 779. http://dx.doi.org/10.3390/v13050779.
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In recent years, the CRISPR/Cas9-based gene-editing techniques have been well developed and applied widely in several aspects of research in the biological sciences, in many species, including humans, animals, plants, and even in viruses. Modification of the viral genome is crucial for revealing gene function, virus pathogenesis, gene therapy, genetic engineering, and vaccine development. Herein, we have provided a brief review of the different technologies for the modification of the viral genomes. Particularly, we have focused on the recently developed CRISPR/Cas9-based gene-editing system, detailing its origin, functional principles, and touching on its latest achievements in virology research and applications in vaccine development, especially in large DNA viruses of humans and animals. Future prospects of CRISPR/Cas9-based gene-editing technology in virology research, including the potential shortcomings, are also discussed.
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Shaikh, Sadiya Bi, and Yashodhar Prabhakar Bhandary. "CRISPR/Cas9 Genome Editing Tool: A Promising Tool for Therapeutic Applications on Respiratory Diseases." Current Gene Therapy 20, no. 5 (December 11, 2020): 333–46. http://dx.doi.org/10.2174/1566523220666201012145731.
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Respiratory diseases are one of the prime topics of concern in the current era due to improper diagnostics tools. Gene-editing therapy, like Clustered regularly interspaced palindromic repeats- associated nuclease 9 (CRISPR/Cas9), is gaining popularity in pulmonary research, opening up doors to invaluable insights on underlying mechanisms. CRISPR/Cas9 can be considered as a potential gene-editing tool with a scientific community that is helping in the advancement of knowledge in respiratory health and therapy. As an appealing therapeutic tool, we hereby explore the advanced research on the application of CRISPR/Cas9 tools in chronic respiratory diseases such as lung cancer, Acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF). We also address the urgent need to establish this gene-editing tool in various other lung diseases such as asthma, Chronic obstructive pulmonary disease (COPD) and Idiopathic pulmonary fibrosis (IPF). The present review introduces CRISPR/Cas9 as a worthy application in targeting epithelial-mesenchymal transition and fibrinolytic system via editing specific genes. Thereby, based on the efficiency of CRISPR/Cas9, it can be considered as a promising therapeutic tool in respiratory health research.
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Gamage, Udani, Kesari Warnakulasuriya, Sonali Hansika, and Gayathri N. Silva. "CRISPR Gene Therapy: A Promising One-Time Therapeutic Approach for Transfusion-Dependent β-Thalassemia—CRISPR-Cas9 Gene Editing for β-Thalassemia." Thalassemia Reports 13, no. 1 (February 6, 2023): 51–69. http://dx.doi.org/10.3390/thalassrep13010006.
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β-Thalassemia is an inherited hematological disorder that results from genetic changes in the β-globin gene, leading to the reduced or absent synthesis of β-globin. For several decades, the only curative treatment option for β-thalassemia has been allogeneic hematopoietic cell transplantation (allo-HCT). Nonetheless, rapid progress in genome modification technologies holds great potential for treating this disease and will soon change the current standard of care for β-thalassemia. For instance, the emergence of the CRISPR/Cas9 genome editing platform has opened the door for precision gene editing and can serve as an effective molecular treatment for a multitude of genetic diseases. Investigational studies were carried out to treat β-thalassemia patients utilizing CRISPR-based CTX001 therapy targeting the fetal hemoglobin silencer BCL11A to restore γ-globin expression in place of deficient β-globin. The results of recently carried out clinical trials provide hope of CTX001 being a promising one-time therapeutic option to treat β-hemoglobinopathies. This review provides an insight into the key scientific steps that led to the development and application of novel CRISPR/Cas9–based gene therapies as a promising therapeutic platform for transfusion-dependent β-thalassemia (TDT). Despite the resulting ethical, moral, and social challenges, CRISPR provides an excellent treatment option against hemoglobin-associated genetic diseases.
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Zhang, Zhihao, Wei Hou, and Shuliang Chen. "Updates on CRISPR-based gene editing in HIV-1/AIDS therapy." Virologica Sinica 37, no. 1 (February 2022): 1–10. http://dx.doi.org/10.1016/j.virs.2022.01.017.
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Nakamura, Watanabe, Ando, Ishihara, and Sato. "Transplacental Gene Delivery (TPGD) as a Noninvasive Tool for Fetal Gene Manipulation in Mice." International Journal of Molecular Sciences 20, no. 23 (November 25, 2019): 5926. http://dx.doi.org/10.3390/ijms20235926.
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Transplacental gene delivery (TPGD) is a technique for delivering nucleic acids to fetal tissues via tail-vein injections in pregnant mice. After transplacental transport, administered nucleic acids enter fetal circulation and are distributed among fetal tissues. TPGD was established in 1995 by Tsukamoto et al., and its mechanisms, and potential applications have been further characterized since. Recently, discoveries of sequence specific nucleases, such as zinc-finger nuclease (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) (CRISPR/Cas9), have revolutionized genome editing. In 2019, we demonstrated that intravenous injection of plasmid DNA containing CRISPR/Cas9 produced indels in fetal myocardial cells, which are comparatively amenable to transfection with exogenous DNA. In the future, this unique technique will allow manipulation of fetal cell functions in basic studies of fetal gene therapy. In this review, we describe developments of TPGD and discuss their applications to the manipulation of fetal cells.
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Nie, Dengyun, Ting Guo, Miao Yue, Wenya Li, Xinyu Zong, Yinxing Zhu, Junxing Huang, and Mei Lin. "Research Progress on Nanoparticles-Based CRISPR/Cas9 System for Targeted Therapy of Tumors." Biomolecules 12, no. 9 (September 5, 2022): 1239. http://dx.doi.org/10.3390/biom12091239.
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Cancer is a genetic mutation disease that seriously endangers the health and life of all human beings. As one of the most amazing academic achievements in the past decade, CRISPR/Cas9 technology has been sought after by many researchers due to its powerful gene editing capability. CRISPR/Cas9 technology shows great potential in oncology, and has become one of the most promising technologies for cancer genome-editing therapeutics. However, its efficiency and the safety issues of in vivo gene editing severely limit its widespread application. Therefore, developing a suitable delivery method for the CRISPR/Cas9 system is an urgent problem to be solved at present. Rapid advances in nanomedicine suggest nanoparticles could be a viable option. In this review, we summarize the latest research on the potential use of nanoparticle-based CRISPR/Cas9 systems in cancer therapeutics, in order to further their clinical application. We hope that this review will provide a novel insight into the CRISPR/Cas9 system and offer guidance for nanocarrier designs that will enable its use in cancer clinical applications.
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Yu, Jiaying, Xi Xiang, Jinrong Huang, Xue Liang, Xiaoguang Pan, Zhanying Dong, Trine Skov Petersen, et al. "Haplotyping by CRISPR-mediated DNA circularization (CRISPR-hapC) broadens allele-specific gene editing." Nucleic Acids Research 48, no. 5 (January 16, 2020): e25-e25. http://dx.doi.org/10.1093/nar/gkz1233.
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Abstract Allele-specific protospacer adjacent motif (asPAM)-positioning SNPs and CRISPRs are valuable resources for gene therapy of dominant disorders. However, one technical hurdle is to identify the haplotype comprising the disease-causing allele and the distal asPAM SNPs. Here, we describe a novel CRISPR-based method (CRISPR-hapC) for haplotyping. Based on the generation (with a pair of CRISPRs) of extrachromosomal circular DNA in cells, the CRISPR-hapC can map haplotypes from a few hundred bases to over 200 Mb. To streamline and demonstrate the applicability of the CRISPR-hapC and asPAM CRISPR for allele-specific gene editing, we reanalyzed the 1000 human pan-genome and generated a high frequency asPAM SNP and CRISPR database (www.crispratlas.com/knockout) for four CRISPR systems (SaCas9, SpCas9, xCas9 and Cas12a). Using the huntingtin (HTT) CAG expansion and transthyretin (TTR) exon 2 mutation as examples, we showed that the asPAM CRISPRs can specifically discriminate active and dead PAMs for all 23 loci tested. Combination of the CRISPR-hapC and asPAM CRISPRs further demonstrated the capability for achieving highly accurate and haplotype-specific deletion of the HTT CAG expansion allele and TTR exon 2 mutation in human cells. Taken together, our study provides a new approach and an important resource for genome research and allele-specific (haplotype-specific) gene therapy.
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Godbout, Kelly, and Jacques P. Tremblay. "Prime Editing for Human Gene Therapy: Where Are We Now?" Cells 12, no. 4 (February 7, 2023): 536. http://dx.doi.org/10.3390/cells12040536.
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Gene therapy holds tremendous potential in the treatment of inherited diseases. Unlike traditional medicines, which only treat the symptoms, gene therapy has the potential to cure the disease by addressing the root of the problem: genetic mutations. The discovery of CRISPR/Cas9 in 2012 paved the way for the development of those therapies. Improvement of this system led to the recent development of an outstanding technology called prime editing. This system can introduce targeted insertions, deletions, and all 12 possible base-to-base conversions in the human genome. Since the first publication on prime editing in 2019, groups all around the world have worked on this promising technology to develop a treatment for genetic diseases. To date, prime editing has been attempted in preclinical studies for liver, eye, skin, muscular, and neurodegenerative hereditary diseases, in addition to cystic fibrosis, beta-thalassemia, X-linked severe combined immunodeficiency, and cancer. In this review, we portrayed where we are now on prime editing for human gene therapy and outlined the best strategies for correcting pathogenic mutations by prime editing.
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Balon, Katarzyna, Adam Sheriff, Joanna Jacków, and Łukasz Łaczmański. "Targeting Cancer with CRISPR/Cas9-Based Therapy." International Journal of Molecular Sciences 23, no. 1 (January 5, 2022): 573. http://dx.doi.org/10.3390/ijms23010573.
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Cancer is a devastating condition characterised by the uncontrolled division of cells with many forms remaining resistant to current treatment. A hallmark of cancer is the gradual accumulation of somatic mutations which drive tumorigenesis in cancerous cells, creating a mutation landscape distinctive to a cancer type, an individual patient or even a single tumour lesion. Gene editing with CRISPR/Cas9-based tools now enables the precise and permanent targeting of mutations and offers an opportunity to harness this technology to target oncogenic mutations. However, the development of safe and effective gene editing therapies for cancer relies on careful design to spare normal cells and avoid introducing other mutations. This article aims to describe recent advancements in cancer-selective treatments based on the CRISPR/Cas9 system, especially focusing on strategies for targeted delivery of the CRISPR/Cas9 machinery to affected cells, controlling Cas9 expression in tissues of interest and disrupting cancer-specific genes to result in selective death of malignant cells.
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Lebek, Simon, Francesco Chemello, Xurde M. Caravia, Wei Tan, Hui Li, Kenian Chen, Lin Xu, Ning Liu, Rhonda Bassel-Duby, and Eric N. Olson. "Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease." Science 379, no. 6628 (January 13, 2023): 179–85. http://dx.doi.org/10.1126/science.ade1105.
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CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients with specific mutations. Here, we describe a cardioprotective strategy potentially applicable to a broad range of patients with heart disease. We used base editing to ablate the oxidative activation sites of CaMKIIδ, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIIδ gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIIδ editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIIδ gene editing may thus represent a permanent and advanced strategy for heart disease therapy.
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Benati, Daniela, Amy Leung, Pedro Perdigao, Vasileios Toulis, Jacqueline van der Spuy, and Alessandra Recchia. "Induced Pluripotent Stem Cells and Genome-Editing Tools in Determining Gene Function and Therapy for Inherited Retinal Disorders." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15276. http://dx.doi.org/10.3390/ijms232315276.
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Inherited retinal disorders (IRDs) affect millions of people worldwide and are a major cause of irreversible blindness. Therapies based on drugs, gene augmentation or transplantation approaches have been widely investigated and proposed. Among gene therapies for retinal degenerative diseases, the fast-evolving genome-editing CRISPR/Cas technology has emerged as a new potential treatment. The CRISPR/Cas system has been developed as a powerful genome-editing tool in ophthalmic studies and has been applied not only to gain proof of principle for gene therapies in vivo, but has also been extensively used in basic research to model diseases-in-a-dish. Indeed, the CRISPR/Cas technology has been exploited to genetically modify human induced pluripotent stem cells (iPSCs) to model retinal disorders in vitro, to test in vitro drugs and therapies and to provide a cell source for autologous transplantation. In this review, we will focus on the technological advances in iPSC-based cellular reprogramming and gene editing technologies to create human in vitro models that accurately recapitulate IRD mechanisms towards the development of treatments for retinal degenerative diseases.
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Lyu, Pin, Luxi Wang, and Baisong Lu. "Virus-Like Particle Mediated CRISPR/Cas9 Delivery for Efficient and Safe Genome Editing." Life 10, no. 12 (December 21, 2020): 366. http://dx.doi.org/10.3390/life10120366.
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The discovery of designer nucleases has made genome editing much more efficient than before. The designer nucleases have been widely used for mechanistic studies, animal model generation and gene therapy development. However, potential off-targets and host immune responses are issues still need to be addressed for in vivo uses, especially clinical applications. Short term expression of the designer nucleases is necessary to reduce both risks. Currently, various delivery methods are being developed for transient expression of designer nucleases including Zinc Finger Nuclease (ZNF), Transcription Activator-Like Effector Nuclease (TALEN) and Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated (CRISPR/Cas). Recently, virus-like particles are being used for gene editing. In this review, we will talk through commonly used genome editing nucleases, discuss gene editing delivery tools and review the latest literature using virus-like particles to deliver gene editing effectors.
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Zhou, Jun, Zhuoying Ren, Jie Xu, Jifeng Zhang, and Y. Eugene Chen. "Gene editing therapy ready for cardiovascular diseases: opportunities, challenges, and perspectives." Medical Review 1, no. 1 (October 1, 2021): 6–9. http://dx.doi.org/10.1515/mr-2021-0010.
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Abstract Gene editing nucleases (GENs), represented by CRISPR/Cas9, have become major tools in biomedical research and offer potential cures for many human diseases. Gene editing therapy (GETx) studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C3 (APOC3), angiopoietin Like 3 (ANGPTL3) and inducible degrader of the low-density lipoprotein receptor (IDOL) have demonstrated the benefits and advantages of GETx in managing atherosclerosis. Here we present our views on this brand new therapeutic option for cardiovascular diseases (CVD).
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Santos, Renato, and Olga Amaral. "Advances in Sphingolipidoses: CRISPR-Cas9 Editing as an Option for Modelling and Therapy." International Journal of Molecular Sciences 20, no. 23 (November 24, 2019): 5897. http://dx.doi.org/10.3390/ijms20235897.
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Sphingolipidoses are inherited genetic diseases characterized by the accumulation of glycosphingolipids. Sphingolipidoses (SP), which usually involve the loss of sphingolipid hydrolase function, are of lysosomal origin, and represent an important group of rare diseases among lysosomal storage disorders. Initial treatments consisted of enzyme replacement therapy, but, in recent decades, various therapeutic approaches have been developed. However, these commonly used treatments for SP fail to be fully effective and do not penetrate the blood–brain barrier. New approaches, such as genome editing, have great potential for both the treatment and study of sphingolipidoses. Here, we review the most recent advances in the treatment and modelling of SP through the application of CRISPR-Cas9 genome editing. CRISPR-Cas9 is currently the most widely used method for genome editing. This technique is versatile; it can be used for altering the regulation of genes involved in sphingolipid degradation and synthesis pathways, interrogating gene function, generating knock out models, or knocking in mutations. CRISPR-Cas9 genome editing is being used as an approach to disease treatment, but more frequently it is utilized to create models of disease. New CRISPR-Cas9-based tools of gene editing with diminished off-targeting effects are evolving and seem to be more promising for the correction of individual mutations. Emerging Prime results and CRISPR-Cas9 difficulties are also discussed.
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Xiu, Kemao, Laura Saunders, Luan Wen, Jinxue Ruan, Ruonan Dong, Jun Song, Dongshan Yang, et al. "Delivery of CRISPR/Cas9 Plasmid DNA by Hyperbranched Polymeric Nanoparticles Enables Efficient Gene Editing." Cells 12, no. 1 (December 30, 2022): 156. http://dx.doi.org/10.3390/cells12010156.
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Gene editing nucleases such as CRISPR/Cas9 have enabled efficient and precise gene editing in vitro and hold promise of eventually achieving in vivo gene editing based therapy. However, a major challenge for their use is the lack of a safe and effective virus-free system to deliver gene editing nuclease elements. Polymers are a promising class of delivery vehicle due to their higher safety compared to currently used viral vectors, but polymers suffer from lower transfection efficiency. Polymeric vectors have been used for small nucleotide delivery but have yet to be used successfully with plasmid DNA (pDNA), which is often several hundred times larger than small nucleotides, presenting an engineering challenge. To address this, we extended our previously reported hyperbranched polymer (HP) delivery system for pDNA delivery by synthesizing several variants of HPs: HP-800, HP-1.8K, HP-10K, HP-25K. We demonstrate that all HPs have low toxicity in various cultured cells, with HP-25K being the most efficient at packaging and delivering pDNA. Importantly, HP-25K mediated delivery of CRISPR/Cas9 pDNA resulted in higher gene-editing rates than all other HPs and Lipofectamine at several clinically significant loci in different cell types. Consistently, HP-25K also led to more robust base editing when delivering the CRISPR base editor “BE4-max” pDNA to cells compared with Lipofectamine. The present work demonstrates that HP nanoparticles represent a promising class of vehicle for the non-viral delivery of pDNA towards the clinical application of gene-editing therapy.
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Padmaswari, Made Harumi, Shilpi Agrawal, Mary S. Jia, Allie Ivy, Daniel A. Maxenberger, Landon A. Burcham, and Christopher E. Nelson. "Delivery challenges for CRISPR—Cas9 genome editing for Duchenne muscular dystrophy." Biophysics Reviews 4, no. 1 (March 2023): 011307. http://dx.doi.org/10.1063/5.0131452.
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Duchene muscular dystrophy (DMD) is an X-linked neuromuscular disorder that affects about one in every 5000 live male births. DMD is caused by mutations in the gene that codes for dystrophin, which is required for muscle membrane stabilization. The loss of functional dystrophin causes muscle degradation that leads to weakness, loss of ambulation, cardiac and respiratory complications, and eventually, premature death. Therapies to treat DMD have advanced in the past decade, with treatments in clinical trials and four exon-skipping drugs receiving conditional Food and Drug Administration approval. However, to date, no treatment has provided long-term correction. Gene editing has emerged as a promising approach to treating DMD. There is a wide range of tools, including meganucleases, zinc finger nucleases, transcription activator-like effector nucleases, and, most notably, RNA-guided enzymes from the bacterial adaptive immune system clustered regularly interspaced short palindromic repeats (CRISPR). Although challenges in using CRISPR for gene therapy in humans still abound, including safety and efficiency of delivery, the future for CRISPR gene editing for DMD is promising. This review will summarize the progress in CRISPR gene editing for DMD including key summaries of current approaches, delivery methodologies, and the challenges that gene editing still faces as well as prospective solutions.
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Yan, Biying, and Yaxuan Liang. "New Therapeutics for Extracellular Vesicles: Delivering CRISPR for Cancer Treatment." International Journal of Molecular Sciences 23, no. 24 (December 12, 2022): 15758. http://dx.doi.org/10.3390/ijms232415758.
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Cancers are defined by genetic defects, which underlines the prospect of using gene therapy in patient care. During the past decade, CRISPR technology has rapidly evolved into a powerful gene editing tool with high fidelity and precision. However, one of the impediments slowing down the clinical translation of CRISPR-based gene therapy concerns the lack of ideal delivery vectors. Extracellular vesicles (EVs) are nano-sized membrane sacs naturally released from nearly all types of cells. Although EVs are secreted for bio-information conveyance among cells or tissues, they have been recognized as superior vectors for drug or gene delivery. Recently, emerging evidence has spotlighted EVs in CRISPR delivery towards cancer treatment. In this review, we briefly introduce the biology and function of the CRISPR system and follow this with a summary of current delivery methods for CRISPR applications. We emphasize the recent progress in EV-mediated CRISPR editing for various cancer types and target genes. The reported strategies for constructing EV-CRISPR vectors, as well as their limitations, are discussed in detail. The review aims to throw light on the clinical potential of engineered EVs and encourage the expansion of our available toolkit to defeat cancer.
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Rabaan, Ali A., Hajir AlSaihati, Rehab Bukhamsin, Muhammed A. Bakhrebah, Majed S. Nassar, Abdulmonem A. Alsaleh, Yousef N. Alhashem, et al. "Application of CRISPR/Cas9 Technology in Cancer Treatment: A Future Direction." Current Oncology 30, no. 2 (February 6, 2023): 1954–76. http://dx.doi.org/10.3390/curroncol30020152.
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Gene editing, especially with clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9), has advanced gene function science. Gene editing’s rapid advancement has increased its medical/clinical value. Due to its great specificity and efficiency, CRISPR/Cas9 can accurately and swiftly screen the whole genome. This simplifies disease-specific gene therapy. To study tumor origins, development, and metastasis, CRISPR/Cas9 can change genomes. In recent years, tumor treatment research has increasingly employed this method. CRISPR/Cas9 can treat cancer by removing genes or correcting mutations. Numerous preliminary tumor treatment studies have been conducted in relevant fields. CRISPR/Cas9 may treat gene-level tumors. CRISPR/Cas9-based personalized and targeted medicines may shape tumor treatment. This review examines CRISPR/Cas9 for tumor therapy research, which will be helpful in providing references for future studies on the pathogenesis of malignancy and its treatment.
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Hou, Yujuan, Guillermo Ureña-Bailén, Tahereh Mohammadian Gol, Paul Gerhard Gratz, Hans Peter Gratz, Alicia Roig-Merino, Justin S. Antony, et al. "Challenges in Gene Therapy for Somatic Reverted Mosaicism in X-Linked Combined Immunodeficiency by CRISPR/Cas9 and Prime Editing." Genes 13, no. 12 (December 13, 2022): 2348. http://dx.doi.org/10.3390/genes13122348.
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X-linked severe combined immunodeficiency (X-SCID) is a primary immunodeficiency that is caused by mutations in the interleukin-2 receptor gamma (IL2RG) gene. Some patients present atypical X-SCID with mild clinical symptoms due to somatic revertant mosaicism. CRISPR/Cas9 and prime editing are two advanced genome editing tools that paved the way for treating immune deficiency diseases. Prime editing overcomes the limitations of the CRISPR/Cas9 system, as it does not need to induce double-strand breaks (DSBs) or exogenous donor DNA templates to modify the genome. Here, we applied CRISPR/Cas9 with single-stranded oligodeoxynucleotides (ssODNs) and prime editing methods to generate an in vitro model of the disease in K–562 cells and healthy donors’ T cells for the c. 458T>C point mutation in the IL2RG gene, which also resulted in a useful way to optimize the gene correction approach for subsequent experiments in patients’ cells. Both methods proved to be successful and were able to induce the mutation of up to 31% of treated K–562 cells and 26% of treated T cells. We also applied similar strategies to correct the IL2RG c. 458T>C mutation in patient T cells that carry the mutation with revertant somatic mosaicism. However, both methods failed to increase the frequency of the wild-type sequence in the mosaic T cells of patients due to limited in vitro proliferation of mutant cells and the presence of somatic reversion. To the best of our knowledge, this is the first attempt to treat mosaic cells from atypical X-SCID patients employing CRISPR/Cas9 and prime editing. We showed that prime editing can be applied to the formation of specific-point IL2RG mutations without inducing nonspecific on-target modifications. We hypothesize that the feasibility of the nucleotide substitution of the IL2RG gene using gene therapy, especially prime editing, could provide an alternative strategy to treat X-SCID patients without revertant mutations, and further technological improvements need to be developed to correct somatic mosaicism mutations.
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Chen, Guofang, Tingyi Wei, Hui Yang, Guoling Li, and Haisen Li. "CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives." Cells 11, no. 19 (September 22, 2022): 2964. http://dx.doi.org/10.3390/cells11192964.
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Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the dystrophin gene and characterized by progressive muscle degeneration, respiratory insufficiency, cardiac failure, and premature death by the age of thirty. Albeit DMD is one of the most common types of fatal genetic diseases, there is no curative treatment for this devastating disorder. In recent years, gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system has paved a new path toward correcting pathological mutations at the genetic source, thus enabling the permanent restoration of dystrophin expression and function throughout the musculature. To date, the therapeutic benefits of CRISPR genome-editing systems have been successfully demonstrated in human cells, rodents, canines, and piglets with diverse DMD mutations. Nevertheless, there remain some nonignorable challenges to be solved before the clinical application of CRISPR-based gene therapy. Herein, we provide an overview of therapeutic CRISPR genome-editing systems, summarize recent advancements in their applications in DMD contexts, and discuss several potential obstacles lying ahead of clinical translation.
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Bischoff, Nadja, Sandra Wimberger, Marcello Maresca, and Cord Brakebusch. "Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?" Cells 9, no. 5 (May 25, 2020): 1318. http://dx.doi.org/10.3390/cells9051318.
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Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing has become a standard method in molecular biology, for the establishment of genetically modified cellular and animal models, for the identification and validation of drug targets in animals, and is heavily tested for use in gene therapy of humans. While the efficiency of CRISPR mediated gene targeting is much higher than of classical targeted mutagenesis, the efficiency of CRISPR genome editing to introduce defined changes into the genome is still low. Overcoming this problem will have a great impact on the use of CRISPR genome editing in academic and industrial research and the clinic. This review will present efforts to achieve this goal by small molecules, which modify the DNA repair mechanisms to facilitate the precise alteration of the genome.
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Huang, Yong, Meiqi Shang, Tingting Liu, and Kejian Wang. "High-throughput methods for genome editing: the more the better." Plant Physiology 188, no. 4 (February 3, 2022): 1731–45. http://dx.doi.org/10.1093/plphys/kiac017.
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Abstract During the last decade, targeted genome-editing technologies, especially clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) technologies, have permitted efficient targeting of genomes, thereby modifying these genomes to offer tremendous opportunities for deciphering gene function and engineering beneficial traits in many biological systems. As a powerful genome-editing tool, the CRISPR/Cas systems, combined with the development of next-generation sequencing and many other high-throughput techniques, have thus been quickly developed into a high-throughput engineering strategy in animals and plants. Therefore, here, we review recent advances in using high-throughput genome-editing technologies in animals and plants, such as the high-throughput design of targeted guide RNA (gRNA), construction of large-scale pooled gRNA, and high-throughput genome-editing libraries, high-throughput detection of editing events, and high-throughput supervision of genome-editing products. Moreover, we outline perspectives for future applications, ranging from medication using gene therapy to crop improvement using high-throughput genome-editing technologies.
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Hussein, Mouraya, Mariano A. Molina, Ben Berkhout, and Elena Herrera-Carrillo. "A CRISPR-Cas Cure for HIV/AIDS." International Journal of Molecular Sciences 24, no. 2 (January 13, 2023): 1563. http://dx.doi.org/10.3390/ijms24021563.
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Human immunodeficiency virus (HIV) infections and HIV-induced acquired immunodeficiency syndrome (AIDS) continue to represent a global health burden. There is currently no effective vaccine, nor any cure, for HIV infections; existing antiretroviral therapy can suppress viral replication, but only as long as antiviral drugs are taken. HIV infects cells of the host immune system, and it can establish a long-lived viral reservoir, which can be targeted and edited through gene therapy. Gene editing platforms based on the clustered regularly interspaced palindromic repeat-Cas system (CRISPR-Cas) have been recognized as promising tools in the development of gene therapies for HIV infections. In this review, we evaluate the current landscape of CRISPR-Cas-based therapies against HIV, with an emphasis on the infection biology of the virus as well as the activity of host restriction factors. We discuss the potential of a combined CRISPR-Cas approach that targets host and viral genes to activate antiviral host factors and inhibit viral replication simultaneously. Lastly, we focus on the challenges and potential solutions of CRISPR-Cas gene editing approaches in achieving an HIV cure.
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Omichi, Ryotaro, Seiji B. Shibata, Cynthia C. Morton, and Richard J. H. Smith. "Gene therapy for hearing loss." Human Molecular Genetics 28, R1 (June 22, 2019): R65—R79. http://dx.doi.org/10.1093/hmg/ddz129.
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Abstract Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.
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Jiang, David J., Christine L. Xu, and Stephen H. Tsang. "Revolution in Gene Medicine Therapy and Genome Surgery." Genes 9, no. 12 (November 26, 2018): 575. http://dx.doi.org/10.3390/genes9120575.
Full textAbstract:
Recently, there have been revolutions in the development of both gene medicine therapy and genome surgical treatments for inherited disorders. Much of this progress has been centered on hereditary retinal dystrophies, because the eye is an immune-privileged and anatomically ideal target. Gene therapy treatments, already demonstrated to be safe and efficacious in numerous clinical trials, are benefitting from the development of new viral vectors, such as dual and triple adeno-associated virus (AAV) vectors. CRISPR/Cas9, which revolutionized the field of gene editing, is being adapted into more precise “high fidelity” and catalytically dead variants. Newer CRISPR endonucleases, such as CjCas9 and Cas12a, are generating excitement in the field as well. Stem cell therapy has emerged as a promising alternative, allowing human embryo-derived stem cells and induced pluripotent stem cells to be edited precisely in vitro and then reintroduced into the body. This article highlights recent progress made in gene therapy and genome surgery for retinal disorders, and it provides an update on precision medicine Food and Drug Administration (FDA) treatment trials.
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Nasrallah, Ali, Eric Sulpice, Farah Kobaisi, Xavier Gidrol, and Walid Rachidi. "CRISPR-Cas9 Technology for the Creation of Biological Avatars Capable of Modeling and Treating Pathologies: From Discovery to the Latest Improvements." Cells 11, no. 22 (November 15, 2022): 3615. http://dx.doi.org/10.3390/cells11223615.
Full textAbstract:
This is a spectacular moment for genetics to evolve in genome editing, which encompasses the precise alteration of the cellular DNA sequences within various species. One of the most fascinating genome-editing technologies currently available is Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and its associated protein 9 (CRISPR-Cas9), which have integrated deeply into the research field within a short period due to its effectiveness. It became a standard tool utilized in a broad spectrum of biological and therapeutic applications. Furthermore, reliable disease models are required to improve the quality of healthcare. CRISPR-Cas9 has the potential to diversify our knowledge in genetics by generating cellular models, which can mimic various human diseases to better understand the disease consequences and develop new treatments. Precision in genome editing offered by CRISPR-Cas9 is now paving the way for gene therapy to expand in clinical trials to treat several genetic diseases in a wide range of species. This review article will discuss genome-editing tools: CRISPR-Cas9, Zinc Finger Nucleases (ZFNs), and Transcription Activator-Like Effector Nucleases (TALENs). It will also encompass the importance of CRISPR-Cas9 technology in generating cellular disease models for novel therapeutics, its applications in gene therapy, and challenges with novel strategies to enhance its specificity.