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A new era of gene editing for the treatment of human diseases.
Kc, M, Steer, CJ
Swiss medical weekly. 2019;:w20021
Abstract
The treatment of human diseases using gene-editing technology has been envisioned for several decades with the realisation that so many were associated with mutations in DNA. The Human Genome Project opened new doors for identifying the genetic bases for human suffering. Research on gene editing has been active since the 1970s, but the technology has seen substantial growth and application just within the past decade. Simply stated, CRISPR technology has become a phenomenon in both biomedical and therapeutics research. Concurrently, cell therapies and pluripotent stem cell research have also been refined and now interfaced with CRISPR technology to enhance and maximise their potential in modelling as well as treatment of human diseases. In this review, we discuss the novel and revolutionary modality of gene editing, as this marks a new era in research and medicine. We also discuss gene-modifying technologies leading to CRISPR, as they are still being used for a wide variety of genomic applications. The modes and challenges for delivery of gene editing components are also discussed. Lastly, we review examples of human diseases that are not only amenable to gene editing techniques, but also show true promise of cure in the early 21st century of genetic correction and gene repair.
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Gene-function studies in systemic lupus erythematosus.
Rosetti, F, de la Cruz, A, Crispín, JC
Current opinion in rheumatology. 2019;(2):185-192
Abstract
PURPOSE OF REVIEW The aim of this review is to discuss recent developments in our understanding of how systemic lupus erythematosus (SLE)-associated genes contribute to autoimmunity. RECENT FINDINGS Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity. Novel research has identified Mac-1 (encoded by ITGAM), CaMK4, and iRhom2 as plausible therapeutic targets in lupus nephritis. SUMMARY The work discussed in this review has broad implications for our understanding of the pathogenesis of SLE and for the development of novel therapeutic strategies.
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CRISPR/Cas9 technology as a potent molecular tool for gene therapy.
Karimian, A, Azizian, K, Parsian, H, Rafieian, S, Shafiei-Irannejad, V, Kheyrollah, M, Yousefi, M, Majidinia, M, Yousefi, B
Journal of cellular physiology. 2019;(8):12267-12277
Abstract
Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR-Cas9) is an RNA-guided gene editing tool which offers several advantageous characteristics in comparison with the conventional methods (e.g., zinc finger nucleases and transcription activator-like effector nucleases) such as cost-effectiveness, flexibility, and being easy-to-use. Despite some limitations such as efficient delivery and safety, CRISPR-Cas9 is still the most convenient tool for gene editing purposes. Due to the potential capability of the CRISPR-Cas9 system in genome editing and correction of casual mutations, it can be considered as a possible therapeutic system in the treatment of disorders associated with the genome mutations and in particular cancer treatment. In this review, we will discuss CRISPR-Cas-based gene editing along with its classifications and mechanism of action. Furthermore, the therapeutic application of the CRISPR-Cas9 system in mutational disorders, delivery systems, as well as its advantages and limitations with a special emphasis on cancer treatment will be discussed.
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Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia.
Hamed, EM, Meabed, MH, Aly, UF, Hussein, RRS
Current drug targets. 2019;(16):1603-1623
Abstract
Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis - the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.
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Non-Viral Delivery To Enable Genome Editing.
Rui, Y, Wilson, DR, Green, JJ
Trends in biotechnology. 2019;(3):281-293
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Abstract
Genome-editing technologies such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENS), and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein system have revolutionized biological research. Each biotechnology consists of a DNA-binding protein that can be programmed to recognize and initiate double-strand breaks (DSBs) for site-specific gene modification. These technologies have the potential to be harnessed to cure diseases caused by aberrant gene expression. To be successful therapeutically, their functionality depends on their safe and efficient delivery into the cell nucleus. This review discusses the challenges in the delivery of genome-editing tools, and highlights recent innovations in non-viral delivery that have potential to overcome these limitations and advance the translation of genome editing towards patient care.
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Future of human mitochondrial DNA editing technologies.
Verechshagina, N, Nikitchina, N, Yamada, Y, Harashima, Н, Tanaka, M, Orishchenko, K, Mazunin, I
Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis. 2019;(2):214-221
Abstract
ATP and other metabolites, which are necessary for the development, maintenance, and functioning of bodily cells are all synthesized in the mitochondria. Multiple copies of the genome, present within the mitochondria, together with its maternal inheritance, determine the clinical manifestation and spreading of mutations in mitochondrial DNA (mtDNA). The main obstacle in the way of thorough understanding of mitochondrial biology and the development of gene therapy methods for mitochondrial diseases is the absence of systems that allow to directly change mtDNA sequence. Here, we discuss existing methods of manipulating the level of mtDNA heteroplasmy, as well as the latest systems, that could be used in the future as tools for human mitochondrial genome editing.
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Attenuation of Inherited and Acquired Retinal Degeneration Progression with Gene-based Techniques.
Cho, GY, Bolo, K, Park, KS, Sengillo, JD, Tsang, SH
Molecular diagnosis & therapy. 2019;(1):113-120
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Abstract
Inherited retinal dystrophies cause progressive vision loss and are major contributors to blindness worldwide. Advances in gene therapy have brought molecular approaches into the realm of clinical trials for these incurable illnesses. Select phase I, II and III trials are complete and provide some promise in terms of functional outcomes and safety, although questions do remain over the durability of their effects and the prevalence of inflammatory reactions. This article reviews gene therapy as it can be applied to inherited retinal dystrophies, provides an update of results from recent clinical trials, and discusses the future prospects of gene therapy and genome surgery.
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Chemistry, manufacturing and controls for gene modified hematopoietic stem cells.
Soni, S, Kohn, DB
Cytotherapy. 2019;(3):358-366
Abstract
Gene modification of hematopoietic stem cells is increasingly becoming popular as a therapeutic approach, given the recent approvals and the number of new applications for clinical trials targeting monogenetic and immunodeficiency disorders. Technological advances in stem cell selection, culture, transduction and gene editing now allow for efficient ex vivo genetic manipulation of stem cells. Gene-addition techniques using viral vectors (mainly retrovirus- and lentivirus-based) and gene editing using various targeted nuclease platforms (e.g., Zinc finger, TALEN and Crispr/Cas9) are being applied to the treatment of multiple genetic and immunodeficiency disorders. Herein, the current state of the art in manufacturing and critical assays that are required for ex vivo manipulation of stem cells are addressed. Important quality control and safety assays that need to be planned early in the process development phase of these products for regulatory approval are also highlighted.
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The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF.
Eckford, PDW, McCormack, J, Munsie, L, He, G, Stanojevic, S, Pereira, SL, Ho, K, Avolio, J, Bartlett, C, Yang, JY, et al
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2019;(1):35-43
Abstract
BACKGROUND Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. METHODS The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. RESULTS To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. CONCLUSIONS This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations.
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[Gene Therapy Office; the Potemkin village of the Ministry of Infrastructure and Water Management].
Kastelein, JJP
Nederlands tijdschrift voor geneeskunde. 2019
Abstract
Within the European Union, the Netherlands has the toughest and most lengthy procedures for issuing environmental permits for clinical gene therapy research. Previous efforts by the Ministry of Infrastructure and Water Management to speed up procedures, such as the establishment of the Gene Therapy Office, have hardly had any effect. The problem is easily solved if the Netherlands opts for a more realistic approach to the alleged environmental risks associated with gene therapy. This requires an adjustment of the lower national environmental regulations. Minister Van Nieuwenhuizen recently became responsible for these regulations, and in July she announced that she would delve into this subject during the summer. The sector hopes that she will take decisive action to adapt the lower national environmental legislation.