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Gene Editing in Gene Therapy: Current Progress and Future Development Trends

Genome editing technologies, especially those based on zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and CRISPR/Cas9 are rapidly entering clinical trials. So far, most of the clinical applications of CRISPR have focused on in vitro editing of cells and then reintroducing them into patients. It is very effective for many diseases including cancer and sickle cell disease. But ideal genome editing will also be applied to the body that requires cell modification for diseases. However, the use of CRISPR technology in vivo can be confused by issues such as off-target editing, inefficient or off-target delivery, and stimulation of counterproductive immune responses. Current research on these issues may provide new opportunities for the use of CRISPR in the clinical field.


The examination of clinical trial data shows that the number of registered trials using genome editors has increased rapidly, and the selected genome editor has changed in recent years. Early trials only used adenovirus-based delivery, and later trials also used adeno-associated virus (AAV). Polymer-mediated plasmid delivery and electroporation delivery in vivo and in vitro also changed over time. The ex vivo delivery of changing cells in the laboratory and then injecting them into patients mainly uses electroporation as a method, but transduction of adenovirus is also applied. So far, systemic delivery is limited to IV-based delivery that uses ZFN-mediated genes to add AAV to hepatocytes.


The use of CRISPR Cas9 in HIV also opens up some new possibilities for HIV treatment. Recent studies have shown that the use of CRISPR components delivered by AAV for gene editing combined with long-acting slow and effective release antiretroviral therapies (LASER ARTs) can eliminate the potentially infectious reservoir of HIV-1 in humanized mice. Although HIV-1 therapy is the earliest gene editing clinical trial and remains the main research focus, many recent trials have focused on tailoring T cells for adoptive cell transfer (ACT) of cancer. There are four types of ACT for gene editing: ordinary T cells, tumor infiltrating lymphocytes (TIL), cells with T cell receptor (TCR), and T cells with chimeric antigen receptor (CAR).


Most in vitro gene editing trials have focused on enhancing CAR engineering T cell therapy. CAR T cell therapy is the first gene transfer therapy approved by the FDA. Many of these clinical trials include gene editors to further enhance CAR engineered T cells. Gamma retrovirus or lentiviral vector mediates CAR gene into T cells. The advantages of these delivery systems are high gene transfer rate and stable expression of CAR. However, these viral vectors randomly integrate CAR into the genome, which may lead to changes in CAR expression, insertional mutagenesis, overexpression of adjacent genes, and gene destruction at the integration site.


The field of genome editing is developing rapidly, and many potential therapies outside of clinical trials are rapidly approaching the field of clinical trials. Many pharmaceutical companies regularly update their development processes to gain insight into upcoming trials. Most of the expected in vitro trials revolve around CAR T treatment and hemoglobinopathies (beta thalassemia and sickle cell disease). In addition to these anticipated trials, another possible area used by ex vivo clinical genome editors is single-gene primary immunodeficiency (PID). Similar to the in vivo ZFN test, PID treatment requires insertion of the correct copy of the gene (or cDNA). However, these PID treatments are ideal for genome editing to some extent, because the standard treatment is usually hematopoietic stem cell transplantation, which means that cells can be modified ex vivo, thus eliminating the delivery problems encountered in the in vivo AAV test.


The rapidly evolving CRISPR toolkit has brought many promising developments to the development of clinical medicine, although there are still some safety and ethical issues that need to be resolved. One of the most interesting areas is the editing of the germline. Although clinical trials have begun in vitro and in humans, there are still some problems that may limit the clinical application of CRISPR in vivo. The most concerned restriction problem is the delivery problem: how to accurately deliver CRISPR, control its activity and limit off-target events.


In the past decade, the rapid development of gene editing technology has provided significant progress for improving human health. The gene editor is in ongoing clinical trials for the treatment of various human diseases including HIV, cancer and blood diseases. With the continuous development of gene editing tools, new treatments for other diseases may emerge. In particular, CRISPR-based gene editing tools are developing rapidly and have been used to produce various modifications in mammalian cells including targeted editing of specific DNA sequences, activation or inhibition of genes of interest, and epigenetic reprogramming of cell identity. However, despite the potential benefits of using gene editing technology for human treatment, in order to better provide patients with safe and effective treatment options, a better understanding of the basic biology of these technologies is needed.


About the author

Creative Biogene provides unique tools and services for research discoveries and product development in the areas of biological and biomedical research. At Creative Biogene, we are dedicated to meeting the needs of clients with high-quality products and services at a reasonable price.

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