Cellular and genetic therapies play a crucial role in regenerative medicine and cancer treatment. The adoptive transfer of genetically modified T cells, such as CAR-T cells, can trigger immune reactivity against cancerous cells. These cellular therapies are associated with severe on / off-target toxicities. These gene switches are regulatory proteins that trigger the transcription to express genes. The gene regulatory proteins control the function of individual gene regulating the gene expression by binding to the promoter gene of the regulatory protein. Gene switch platforms play a significant role for the enhancement of engineered T-cell therapies by incorporating the on/off mechanism.
Today, several research papers are underway to assess the efficacy of small gene safety switches for multitude of cell-based interventions. Moreover, gene switches play an important role in regulating the expression of transgenes in gene-based therapies, eliminating the requirement of additional protein components. Also, these switches are further contributing to increasing the proliferation of activated cell therapies, thereby helping patients live a quality life. Technological advancements have made it possible to have reversible control of cellular products either through protein-based regulators supply or by removal of small molecules and through physical stimuli such as ultrasound, light, and heat. Driven by this factor, it is expected that the genetic switch market is expected to grow at a CAGR of 11.5% in the future, according to Roots Analysis
Gene switches or molecular switches refer to the use of genetic engineering to control targeted genes in an organism to achieve desired genes. In gene switching, targeted genes are regulated through a molecular switch system. This switching mechanism either turns on or deactivates turn-off specific functions.
Each regulatory gene has a promoter region at the upstream end. When the gene is transcribed into mRNA, the promoter region will bind to the transcription factors (special proteins). These transcription factors recruit RNA polymerase to bind to the specific gene—creating a messenger RNA from the specific gene. At the same time, mRNA is then processed to make the gene’s protein. Meanwhile, the regulatory “gene switch” regions found the upstream site of the promoter region that further provides additional genetic control.
These molecular switches assist transcription factors in binding at the promoter site. Next to the gene, multiple switches are present that trigger different switches at a different time in different cells during development, allowing genetic products to express at specific place and time. Gene switches have played a crucial role in delivering adoptive cell therapy.
Gene therapy can help to compensate for alteration in different ways;
1. Gene Transfer Therapy: The therapy helps to introduce genetic material into the cell machinery. If any altered gene results in the manufacturing of a faulty protein or missing protein, gene therapy helps to introduce a functional gene copy into the cell to recover the function of the faulty protein. At the same time, gene therapy can also introduce a different gene that commands protein synthesis and helps cells function properly.
2. Genome Editing: This is an advanced technique that is actively used for gene therapy. However, instead of adding a new gene into the cell, the genome editing technique introduces gene-editing tools that alter existing DNA inside the cell. The technology allows the removal and addition of genes at specific locations. CRISPR-Cas9 is one of the popular types of genome editing that is used in genome editing.
Application of CRISPR-Based Gene Switches
With the introduction of gene switches, extended gene circuits can be built to provide a precise function and offer a wide range of applications, such as gene regulation, expressions, and genetic therapies. This further led to the introduction of a large number of CRISPR-based genetic circuits that incorporate CRISPR-based molecular switches in three significant ways;
1. Light/ligand inducible genetic switches
2. Gene switches have feedback and non-linear behavior
3. Multi-input biocomputation circuit
Continuous exposure to ionizing radiation and carcinogens leads to damage to DNA inside the cell. However, the discovery of gene switches helps to hijack the natural cell process to reinstall the correct gene and help cell machinery in the repairing process. The development of genetic switches such as CRISPR-Cas9 serves as a perfect solution.
The tool introduces DNA breaks at specific sites in the genome. While CRISPR-Cas9 was being used by bacteria to insert DNA breaks into viral genomes in order to avoid infection, scientists may be able to use CRISPR-Cas9 to induce DNA breaks into eukaryotic genomes in order to modify genes. Researchers leverage the CRISPR-Cas9’s potential to accurately bind on DNA targets. The integration of gene switch alter the nuclease programme redirect them to break certain DNA targets and label them for repair. The gene switch platforms have significant properties allowing the creation of cell-based therapies. The application of gene switches has been broadly divided into two main categories such as:
Gene switches can regulate endogenous genes, which led to the development of several gene therapies. The diseases that are caused due to uncoordinated or sub-optimal gene expression or defective gene products can be treated using gene switches, allowing recovery over endogenous gene locus. Furthermore, gene switches also allow researchers to either switch on or off a gene of interest at a particular time.
Gene switches can be used as an external inducible gene production mechanism to control uncontrolled or over-expression of exogenous genes. The primary gene switch applications include:
● Management of Therapy Related Toxicities
Cell-based therapies employing genetically engineered cells, such as TCR-based therapies and CAT-Ts, have shown promising results during clinical trials. Despite the advantages of gene therapies, there are several adverse side effects of cell therapies leading to toxicity. Thus, some research is underway to evaluate safety switches for different cell-based interventions such as FITC, rapamycin, rimiducid, and dasatinib.
● Cell Proliferation
Gene switches have been extensively used for improving cell proliferation and extension of the lifespan of activated cell therapies, allowing durable responses to therapies. Gene switches such as the GoCAR technology of Beliicum can enhance CAR-T Cell proliferation by resisting exhaustion and accelerating the production of immunomodulatory cytokines.
Currently, the pharmaceutical market players are showing their interest in the development of different types of gene switches for a broad range of applications. They are mainly focused on the regulation of gene expression, treatment associated with toxicity, and other applications.
There are a variety of big, medium-sized, and small businesses in the landscape. Additionally, the majority of gene switch platforms are employed to lessen the side effects of CAR-T cell therapy. Furthermore, business leaders work together to improve the current offers in this subject, it is always changing. Driven by the factors, the gene switch market is expected to grow at a CAGR of 11.5% in upcoming years
Autolus Therapeutics, aceRNA Technologies, Bellicum Pharmaceuticals, Kiromic Biopharma, Precigen, panCELLa, and Sangamo Biosciences are important participants in the gene switch market.
Gene switch has become the key component of the biological revolution. These gene therapy molecular switches help to harness different types of genetic molecules within cells, such as RNA, DNA, and protein. Molecular technologies such as genome editing help alter these intracellular components for analysis and correction.
For example, CRISPR and restriction malaria—the genetically modified malaria-carrying mosquitoes through gene editing technologies may help in the reduction of disease levels by spreading modified genes using gene switches across a population of mosquitoes.
§ Next Generation Pharmaceuticals
The introduction of new gene switches and small molecules can be used in designing medicinal drugs with multiple targeted structures.
For example, regulation of cellular aging and Senolytics is seen as an inevitable physiological process and not a target for therapeutic development. However, Senolytics (a family of tiny chemicals) may reduce or even get rid of old cells, which can lead to tissue damage, intracellular inflammation, and malfunction. This might postpone the onset of age-related illnesses.
A cellular therapy switch is a biological product that is obtained from living cells. This is used to replace or repair damaged tissues or cells. Therapies such as CAR-T cell therapy have the potential to reprogram the T-cells to target cancerous tumor cells.
Gene switches have become the crucial component of gene therapies, making it possible to modify the gene or protein function and cure patients from genetic disorders. With ongoing technological advancements and research on gene switches, the market is expected to boost in the future and provide innovative solutions to treat rare diseases.
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