Essay on Gene Therapy and DNA Vaccines

The milestone discovery of DNA led to many other discoveries in disease and disorder treatments; the main interest being cancer. Origin of cancer is sometimes genetic where DNA damage occurs during replication which cannot be corrected due the presence of mutated DNA repair genes.

The cell growth is also initiated due to the absence of functional cell cycle check-point genes. These mutated genes or downstream genes are good sites for gene therapy.

The breakthrough was with the use of genetic material (genes) to treat diseases where the ‘genes’ are able to express protein or interfere with the protein synthesis within the cell. This phenomenon is termed as ‘Gene Therapy’. DNA vaccines are the latest technique in gene therapy where genes for tumor specific antigens are injected intramuscularly as naked plasmid DNA where they initiate protein synthesis.

The immune system can be manipulated by gene therapy to help body’s natural defences to recognise and target cancer cells. ‘The effectiveness to screen for antigens rapidly and to design specific types of expression constructs has made the study of DNA vaccines a valuable field for immunotherapy of cancer’.

An inbuilt ability is present in DNA vaccines which activates multiple pathways of innate immunity and guides defined antigens accompanied by specific activator molecules. DNA vaccines not only have an inbuilt ability to activate multiple pathways of innate immunity, but also offer a unique opportunity to guide defined antigens, accompanied by specific activator molecules, through a patient’s compromised immune system.

DNA vaccines are established as bacterial plasmids that are engineered to express disease-specific antigen using promoter elements that are active in mammalian cells. A transcriptional terminator is also present to terminate transcription in mammalian cells and a selectable marker to facilitate production of plasmids in transformed bacterial cells.

CD4+ T cells play an important role in activating innate immunity against weak tumor antigens. T cell help can be taken from the undamaged anti-microbial selection.

Heterologous prime-boost strategies have been helpful in accelerating cellular immune responses which is very effective in cancer. This phenomenon generates large number of secondary antigen-specific T-cells which are delivered in sequence using different vectors. T- cells are increased in proportion and then gradually are transformed into antigen-specific memory T-cells.

There are many methods of delivery of DNA vaccines of which electroporation is the most efficient as it increases both antigen activity and inflammatory activity. Another popular method of delivery is the priming of DNA with viral vectors.

Viral vector delivery is not readily applicable to cancer where pre-existing or induced antivector immunity would undermine repeated boosting efficacy. Other methods include formulations with nanoparticles, microparticles and liposomes. Delivery with electroporation, particle bombardment, jet injection and tattooing are other methods of delivery of which electroporation are the most successful. Vaccine delivery should avoid the skin route as it may cause certain issues or the vaccine may not be very effective.

Advantages of DNA vaccines include high transfection efficiency and stability, capability to encode a number of immunological components, induce cellular and humoral immune responses and lower cytotoxicity.

Every technology has its drawbacks so has DNA vaccines. These cannot be produced in large quantities, have toxic side effects, limitations to transgene size, poor immunogenicity and are very expensive to produce.

Future work

DNA vaccines require improvements in antigen expression and delivery systems and additional requirements for effective immunity against poorly immunogenic tumor antigens.

To attain positive results cancer vaccines should have the finest tumor antigens with efficient immunotherapy agents and delivery approaches. The goal of DNA vaccination will be the development of effective immunization strategies against previously established tumors.

Strategies to improve antigen expression, inclusion of adjuvants in the formulation, or as immune modulators to improve the immunogenicity, and the use of next-generation delivery methods are the next intensive investigation. DNA vaccines based on antigenic epitopes fused to immunogenic adjuvants can induce resistance to tumour challenge.

The other improvements should be made in potent immune responses and clinical efficacy. DNA vaccines need to be combined with other treatment modalities because of their tolerance to tumour antigens. Vaccines need to be combined with other treatment modalities because of its tolerance to tumour antigens.

For efficient immunogenicity DNA delivery methods such as gene gun and electroporation should be improved with the use of new adjuvants. Developments in new viral vectors will lead to more treatment options.

For cancer vaccines, measurements in blood provide only a limited snapshot of CD8+ T-cell responses, and skin challenges could be helpful. Combinations with a judicious use of chemotherapy, which could have differential effects on suppressor mechanisms, are an emerging new approach. The ultimate goal of changing tumor behaviour for patients is in sight but flexible small trials are still needed to guide the way.

The induction of effective immunity against the chosen target with no damage to autoimmunity is the next important breakthrough for vaccination. There is still much to do in terms of optimizing vaccine design, activation and selecting appropriate target antigens, improving immune recruitment, and delivery technology.

With all these issues still wide open, it warrants through study in terms of DNA vaccination as a part of gene-therapy. It would be a challenging research to be able to invent or discover a permanent cure for the deadly cancer.

By

Laavanya Rayaprolu

Email: rlaavanya-at-yahoo.com