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Year : 2013  |  Volume : 5  |  Issue : 2  |  Page : 83-87

Gene therapy: An overview

Department of Oral Pathology and Microbiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Gorimedu, Puducherry, India

Date of Web Publication3-Jan-2014

Correspondence Address:
Sudip Indu
Department of Oral Pathology and Microbiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Indira Nagar, Gorimedu, Puducherry - 605 006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-8844.124249

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Gene therapy "the use of genes as medicine" involves the transfer of a therapeutic or working copy of a gene into specific cells of an individual in order to repair a faulty gene copy. The technique may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. The objective of gene therapy is to introduce new genetic material into target cells while causing no damage to the surrounding healthy cells and tissues, hence the treatment related morbidity is decreased. The delivery system includes a vector that delivers a therapeutic gene into the patient's target cell. Functional proteins are created from the therapeutic gene causing the cell to return to a normal stage. The vectors used in gene therapy can be viral and non-viral. Gene therapy, an emerging field of biomedicine, is still at infancy and much research remains to be done before this approach to the treatment of condition will realize its full potential.

Keywords: Genes, oral cancer, viral and non-viral vector

How to cite this article:
Indu S, Ramesh V, Oza N, Prashad KV. Gene therapy: An overview. J Orofac Sci 2013;5:83-7

How to cite this URL:
Indu S, Ramesh V, Oza N, Prashad KV. Gene therapy: An overview. J Orofac Sci [serial online] 2013 [cited 2023 Jan 31];5:83-7. Available from:

  Introduction Top

Gene therapy is the insertion, alteration or replacement of a defective gene within an individual cell and biological tissues by a corrected version of genetic sequence, such as to eliminate a disease for the lifetime of the patient.

Gene therapy basically involves correction of a defective mutated gene through insertion of functional genes into specified genomic locations.

The novel thought of gene therapy was initially put forward by Cusack and Tarner in the year 1998.

  Types of Gene Therapy Top

  1. Germ line gene therapy
  2. Somatic gene therapy

Germ line gene therapy

A mode of treatment where genes are incorporated into the reproductive cell/tissues of the organism. In this technique, functional healthy genes are delivered to the egg/sperm cells.

Two different types of treatment modalities have been advocated:

  1. Alteration/modification of genetic sequence of reproductive tissues before fertilization.
  2. Modification of genetic sequence at the blastomere stage.

Germ line gene treatment is still in its infancy and a lot of research and clinical trials are underway, such as to make it a part of main stream medicine.

Somatic gene therapy

It is the alteration of genes in human somatic cells to treat a specific disorder. [1] Involves incorporation of functional genetic material into body cells and tissues other than the reproductive tissues. It is here, the risk of transfer of mutated genes to the next generation is considerably minimized. When compared to the germline gene therapy, this mode of treatment can be carried out easily.

Numerous experimentation and clinical trials are being carried out in gene therapy, such that it can slowly but surely form a novel medical approach in successfully treating chronic ailments such as oral cancer, hemophilia and muscular dystrophy.

  Vectors in Gene Therapy Top

Viruses are obligate intra-cellular parasites, with great specificity to a particular cell type. They are very efficient at transfecting their own deoxyribonucleic acid (DNA) into the host cell, which is expressed to produce new viral particles. Transfer of therapeutic gene into the host cell and tissue is done by the use of a vector. Viruses represent highly evolved natural vectors for the transfer of foreign genetic information into cells. [2] This attribute has led to extensive attempts to engineer recombinant viral vectors for the delivery of therapeutic genes into diseased tissues. Viral vectors are a tool quite frequently used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (in vivo) or in cell culture (in vitro).

Ideal requirements for a viral vector would be:

  • Should not be immunogenic.
  • Should be stable and easily reproducible.
  • Increased longevity of expression.

Vectors are broadly comprised of two types:

  • Viral vectors.
  • Non-viral vectors.

Viral method

Virus/viral vectors: All viruses bind to their hosts and introduce genetic material into the host cell as part of the replication cycle.

Certain common types of virus groups used as vectors are:

  • Retro virus.
  • Herpes virus.
  • Adeno virus.
  • Adeno associated virus (AAV).

Retro virus

The genetic material in retroviruses is in the form of ribonucleic acid (RNA) molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell with a high degree of efficiency. [1] The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.

Now as the genetic material of the virus has been inserted, the host cell has been modified to contain the new genes. If this host cell divides later, its descendants of the host cell contain the new genes.

One of the side-effects of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted causing insertional mutagenesis. If the gene happens to be one regulating cell division, uncontrolled cell division can occurs leading to cancer.

Adeno virus

Adenoviruses are viruses which carry their genetic material in the form of double-stranded DNA. When these viruses infect a host cell, they introduce their DNA molecule into the host. The DNA molecule is left free in the nucleus of the host cell and instructions in this extra DNA molecule are transcribed just like any other gene. The difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene. This vector system has been one of the first gene therapy products to be formulated to treat cancer. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. [3]

Herpes simplex virus (HSV)

The HSV is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate.

Adeno-associated viral vectors

AAVs, from the parvovirus family, are small viruses with a genome of single stranded DNA. These viruses can insert genetic material at a specific site on a chromosome. There are a few disadvantages of using AAV, including the small amount of DNA it can carry and the difficulty in producing it. This type of virus is used, because it is non-pathogenic. In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus.

  Non-Viral Vectors Top

Non-viral methods present certain advantages like simple large scale production and low immunogenicity. Various methods known are:

Physical transfection


Electroporation involves short pulses of high voltage to carry DNA across the cell membrane through temporary formation of pores in the cell membrane.

Here the only side-effect that could arise was the localized progressive necrosis leading to increase cell death.

Newer method of electron-avalanche transfection where DNA was efficiently delivered through short pulses resulting in insertional efficiency and decreased cellular damage.

i. Gene gun

DNA is coated with gold particles and is loaded into a device with generation of force to achieve penetration of DNA into cells-leaving gold on the stopping disk.

ii. Sonoporation

Uses ultrasonic frequencies, by using acoustic cavitation, which disrupts cell membrane and allow DNA to move into cells.

iii. Magnetofecation

DNA is complexed with magnetic particles and a magnet is placed underneath the tissue culture dish to bring DNA complex into contact with a cell monolayer.

  Chemical Methods Top

Various chemical delivery systems include

  1. Oligonucleotides
  2. Lipoplexes and poly plexes
  3. Dendrimers
  4. Inorganic nanoparticles such as gold, silica and iron oxide are used for gene delivery.

  Gene Therapy in the Management of Oral Cancer Top

Oral squamous cell carcinoma is a genetic disease in which genes, which control cell growth and apoptosis are mutated, allowing cells to acquire the ability to invade and metastasize.

Gene therapy can selectively attack cancer cells while sparing the normal tissues.

Gene therapy procedure involves the following steps:

  • Identification, isolation and amplification of the gene.
  • In vitro culture of tissue cells from the patient to be treated.
  • Transfer of therapeutic gene into cultured cells via vector.

Currently, gene therapy for management of oral cancer involves the following techniques:

Addition gene therapy

  • Approach is to regulate tumor growth by introducing tumor suppressor genes that inactivate the carcinogenic cells.
  • P53 alteration is an early event in oral carcinogenesis. Thus, p53 is the most commonly used gene with adenovirus as viral vectors. Studies are being carried out on adenovirus vector Ad5CMV-p53, which is applied by intramucosal injection followed 2 h later by a mouthwash. From the next day, it is administered as a mouthwash twice daily for 2-5 days. This treatment is repeated every 28 days and has shown a capacity to inhibit disease progression in precancerous lesions with no toxic effects.
  • Other tumor suppressor genes that could be introduced into tumor cells were Rb gene, mda-7 which was found to inhibit the cell cycle of tumor cells, inducing apoptosis and triggering suppression of tumor growth.

Genetherapy using oncolytic virus

  • The term "oncolytic viruses" applies to viruses that are able to replicate specifically in and destroy tumor cells and this property is either inherent or genetically-engineered. [4] It is one of the most promising approaches in gene therapy where adenovirus ONYX-015, which did not grow in normal cells but grew in cells without p53. This has been used to control oral cancer lesions. Intravenous injection of this vector produces important tumor regression and improves survival in the presence of metastasis. These oncolytic viruses have shown enhanced activity when combined with chemotherapy. Patients with precancerous lesions were treated with Advexin mouthwash, which also administers p53 by means of an adenovirus, showing a marked decrease in the number and aggressiveness of precancerous cells. [5]

Suicide gene therapy

  • Here the genes are introduced into the host that stimulate the generation of products that are toxic for the cells. Suicide genes permit the expression of enzymes that can transform non-toxic drugs into cytotoxic substances. Gene transfer of HSV thymidine kinase gene via adenovirus vector in combination with ganciclovir administration may be a good therapeutic option for oral cancer. [6]
  • One of the main drawbacks of suicide gene therapy is the poor distribution of the vector within the tumor. [6],[7]

Gene therapy to inhibit tumor angiogenesis

  • Use of microencapsulated cells in antiangiogenic cancer therapy involves the release of therapeutic proteins to encapsulate recombinant cells. Micro encapsulated cells are capable of secreting angiostation an important angiogenic inhibitor. Angiostatin receptors present adenosine triphosphate synthase on the surface of human endothelial cells, as in the case of αvβ3-integrin and vitronectin. This enables angiostatin to be localized in the tumor instead of organs near the implantation site of the capsule. This form of treatment is a prolonged therapy that requires repeated doses and is associated with a high degree of toxicity. [6],[7]
  • Investigators are also developing vaccines against receptor 2 of the vascular endothelial growth factor, also known as fetal liver kinase-1, with the resulting inhibition of angiogenesis, tumor growth and metastasis. This vaccine also appears to be useful in the treatment of tongue metastasis of oral cancer.


  • The aim of immunotherapy is to increase the patient's immune response to the tumor.
  • Studies have shown that interleukin (IL-2) administration activates T lymphocytes and natural killer cells and that these in turn activate tumor necrosis factor α (TNF-α). Radiosensitivity to γ radiation and chemosensitivity to 5-fluoracil were reported in and after the suppression of nuclear factor-kappa B (NF-kB) activity, which activates the antiapoptotic proteins TNF. NF-kB also increases the expression of proinflammatory cytokines, e.g., IL-1 α, IL-6 and IL-8 and of enzymes that degrade matrix metalloproteinase-9. NF-kB appears to contribute towards the progression and metastasis of various cancers, including oral cancer, therefore its inhibition may be a useful coadjuvant treatment in oral cancer. [7]

Excision gene therapy

Basic aim of this therapy is to remove defective oncogene, thus inhibiting the growth of tumor cells.

Antisense RNA therapy

Antisense RNA can prevent the activity of oncogene, including myc, fos and ras and can also inhibit virus HSV-1, human papilloma viruses, human T lymphotropic virus. [7] Conventional use of this technique is limited by the difficulty of introducing a sufficient quantity of antisense molecules to inhibit tumor growth.

Studies are under way in patients with advanced oral cancer to evaluate the safety and biological effects of administering liposome-mediated intratumoral epidermal growth factor receptor by means of antisense gene therapy. Results have been positive, showing low toxicity and high efficacy.

Limitations of gene therapy

Leaving aside technical constraints, there are many ethical issues which need consideration during administration of gene therapy.

  1. Difficulty in treating polygenic disorders: In general, it is the single gene disorders, which may have best chances of being treated by gene therapy. However, multi-gene disorders such as cardiovascular diseases, hypertension etc. will require much more specialized techniques and thorough understanding of gene therapy regime before it can be formulated as a novel medical therapy.
  2. Immune reaction by the host cell to the vector as the produces antibodies to the vector as it recognizes the vector as a foreign substance.
  3. Efficiency of viral vectors: Factors like specificity of action in targeting specific tissues, tendency to acquire pathogenicity are important confounding factors.
  4. Repeated administration: because of short lived nature of therapeutic gene introduced, multiple administrations may be required for successful treatment approach.

  Conclusion Top

Gene therapy is an emerging field of biomedicine, with a potential to form a definitive treatment for oral cancer and other chronic ailments by offering greater effectiveness and possibly reducing the mortality rate.

However, in the future the combination of gene therapy with chemotherapy and immunotherapy may form one of the most promising fields of research in the management of human diseases.

  References Top

1.Jorde LB, Carey JC, Bamshad MJ, White RL. Genetic screening, genetic diagnosis and gene therapy. In: Copland B, editor. Medical Genetics. 2 nd ed. Missouri: Mosby; 1999. p. 283-8.  Back to cited text no. 1
2.Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: The art of turning infectious agents into vehicles of therapeutics. Nat Med 2001;7:33-40.  Back to cited text no. 2
3.Wilson JM. Gendicine: The first commercial gene therapy product. Hum Gene Ther 2005;16:1014-5.  Back to cited text no. 3
4.Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006;98:298-300.  Back to cited text no. 4
5.Vattemi E, Claudio PP. The feasibility of gene therapy in the treatment of head and neck cancer. Head Neck Oncol 2009;1:3.  Back to cited text no. 5
6.Saraswathi TR, Kavitha B, Vijayashree Priyadharsini J. Gene therapy for oral squamous cell carcinoma: An overview. Indian J Dent Res 2007;18:120-3.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.Ayllón Barbellido S, Campo Trapero J, Cano Sánchez J, Perea García MA, Escudero Castaño N, Bascones Martínez A. Gene therapy in the management of oral cancer: Review of the literature. Med Oral Patol Oral Cir Bucal 2008;13:E15-21.  Back to cited text no. 7

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