The Cell and Gene Therapy Renaissance
How cell and gene therapy, along with viral vectors, are shaping the future of medicine
In recent years, cell and gene therapy (CGT) has become a beacon of hope within the biomedical field due to its potential to revolutionize how we treat diseases. Cell therapy involves the transfer of live, intact cells with a relevant function into a patient to replace or repair damaged tissue and cells. On the other hand, gene therapy is centered around modifying the genome of targeted cells. The new genetic material is administered either directly into the patient's body (in vivo) or into cells harvested from the patient that are subsequently reintroduced (ex vivo or cell-based gene therapy). This enables scientists to replace missing or malfunctioning genes, introduce genes capable of fighting disease, and turn off problematic genes.
The rise of cell and gene therapy
A compelling feature of CGTs is their significant growth within life sciences, offering newfound hope to patients with little to no therapeutic options. In recent years, it has yielded remarkable success in various medical conditions, including treatments for genetic disorders, rare diseases, and cancer. One example is CAR-T cell therapy, which is a personalized cell-based gene therapy. It involves harvesting a patient’s T-cells and re-engineering them to produce surface chimeric antigen receptors (CARs). CARs bind to specific antigens on cancer cells and cause cell death.1 While it is still early days for CAR-T therapy, it has already set the stage for further discovery.
The engine behind gene therapy
The introduction of genetic material in gene therapy and cell-based gene therapy requires the use of vectors. Vectors act as a delivery system, transporting genetic material to target cells and protecting it from degradation. The success of these therapies hinges on their efficiency and precision.
Both non-viral and viral vectors can be used. Non-viral vectors require physical or chemical methods—such as electroporation, lipofection, and microRNA—to deliver genetic material. While they exhibit reduced cytotoxicity, immunogenicity, mutagenesis, and costs compared to their viral counterparts, they have yet to demonstrate the ability to provide long-term therapeutic effects. As such, viral vectors are the preferred and most common vehicle for gene therapies.2
Viral vectors capitalize on a virus's innate ability to enter host cells efficiently. These vectors are made up of the viral capsid for transportation, the desired transgene, and a regulatory cassette containing genes that regulate transgene expression. The parts of the viral genome that are not needed for delivery are never used, leaving only safe components that cannot induce a viral reaction.2
Viral vectors in action
Several viral vectors are commonly used, each possessing unique features and applications. The most common viral vector systems are retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses (AAV).
Retroviral vectors can stably integrate their genetic material into the host genome to form a provirus. While this allows for sustained gene expression, it carries the risk of insertional mutagenesis, which can lead to tumor development. These vectors are also limited by their inability to infect non-dividing cells. These limitations have shifted focus to alternate viral vector systems.2
Lentiviral vectors are a subclass of retroviruses that insert their genetic material into dividing and non-dividing cells. They are characterized by reduced immunogenicity compared to other retroviral vectors and a lower likelihood of insertion near proto-oncogenes, limiting the risk of insertional mutagenesis. These attributes make them an ideal choice for various gene delivery applications.2
Adenoviral vectors can also infect dividing and non-dividing cells. These vectors are advantageous since they deliver many genome copies per host cell with high protein expression levels. However, their clinical applicability is limited since they can elicit a strong inflammatory response due to past exposures, which are common due to their ubiquitous nature. Additionally, they cannot integrate into the host genome, resulting in a diluted treatment effect in dividing cells. This limits their utility for disorders that require sustained gene expression.2
Like adenoviral vectors, AAV vectors can infiltrate dividing and non-dividing cells without integrating into the host genome. While they have a smaller genome capacity, reduced protein levels, and delayed onset of expression, they boast the potential for longer-lasting gene expression. AAV vectors also induce weaker immune responses, minimizing the potential for inflammation and increasing efficacy. Due to their safety and ability to infect a broad range of cells, AAV vectors are a leading platform for genetic therapy.2
Looking into the future
Over time, medical advancements have improved the prognosis of many conditions. CGTs are aiding in this progress and paving the way for further innovation. Ongoing CGT research will likely prioritize improving the safety profile of viral vectors to minimize immune responses and off-target effects. Efforts to increase their accessibility—by focusing on regulatory hurdles, affordability, and infrastructure requirements—will ensure that patients of diverse backgrounds can benefit from these therapies. Furthermore, CGTs will likely expand beyond rare and genetic disorders to encompass a broader range of diseases. These transformative therapies hold the potential to redefine how we approach and manage a host of conditions, offering the chance at a healthier future for all.
References:
Miliotou N. Androulla and Papadopoulou C. Lefkothea. "CAR T-cell therapy: A new era in cancer immunotherapy". Curr Pharm Biotechnol 19, 5-18 (2018).
Ghosh S, Brown AM, Jenkins C, Campbell K. "Viral vector systems for gene therapy: A comprehensive literature review of progress and biosafety challenges". Appl Biosaf 25, 7-18 (2020).
