Gene therapy and prostate cancer
The subject of gene therapy first came up in the late 1960s and early 1970s, and is still the latest innovation in the field of medicine. Gene therapy works on the basis of manipulating the basis of human inheritance, the DNA (Saraswat et al. 2009). In a lot of medical conditions, the underlying problem is an abnormality in the gene which is the basic building block of inheritance and transfer of information from generation to generation. Gene therapy can be broadly defined as a branch of biomedical engineering which deals with the insertion, withdrawal or alteration of DNA (gene) within specific cells in order to treat a medical condition (Mammen et al. 2007). Usually, the most common form of gene therapy involves the insertion of an artificially synthesized gene into a specific genetic locus to replace a transformed gene.
The first gene therapy was conducted on a four-year old girl, Ashanti DeSilva, on the fourteenth of September, 1990. The procedure was conducted by researchers at the United States National Institutes of Health on the patient who had a disorder of the immune system, specifically Severe Combined Immune Deficiency (SCID). The procedure was successful as the girl was able to recover but the effects showed only for a short period of time. Since then, there have been several modifications to the concept. Newer versions of the procedure attempt to directly repair errors in the products of the damaged or altered genes. Repairs are made on the messenger RNA which is produced from the altered gene (Baoutina et al. 2007).
The death of a patient, Jesse Gelsinger, undergoing gene therapy trial for ornithine transcarboxylase deficiency (OTCD) in 1999 brought about a minor setback in the development of gene therapy. This occurrence resulted in the Food and Drug Administration suspending all clinical trials on gene therapy as the ethical implications of the whole procedure were reassessed again. However, after some time, the ban was lifted and subsequent trials were much more successful. Since 2001, there have been significant achievements in the history of development of gene therapy. Several patients have been successfully cured of conditions such as metastatic melanoma and diseases affecting the myeloid cells.
Gene therapy can be broadly classified into two types: germline therapy and somatic gene therapy (Saraswat et al. 2009). Germline gene therapy involves the modification of the genetic code of germ cells (egg or sperm) by introducing already altered or artificially synthesized genes which are incorporated into the genome of these cells. This form of genetic modification is heritable and can be passed to future offsprings. The second category, somatic gene therapy, involves the alteration of the genome of the somatic cells of the individual undergoing the treatment. Every alteration or modification made in somatic gene therapy is restricted to the patient and cannot be transferred to future offsprings. This form of gene therapy holds several possibilities and counters a lot of ethical considerations.
The gene is situated in a double helix structure which cannot be seen with the aid of the naked eye. It can only be observed with the aid of very powerful microscopes. Since this is the case, the problem of how to alter what cannot be seen ordinarily now arises and this can be countered with the use of materials called vectors (Saraswat et al. 2009). The vectors bear the new gene which goes into the cell to replace or repair the damaged gene. In most cases, viruses are used as vectors. Viruses have predilection for the genetic material of the host cell it infects. Usually, when the virus enters the cell, it incorporates its genetic material into the host cell’s DNA or RNA as part of its replication cycle. The virus’ genetic material then takes over the cell’s metabolic machinery as it now controls the command centre of the cell. The virus can then instruct the cell to provide the requirements for the production of additional copies of the virus.
Apart from viruses, vectors can be made from naked DNA, oligonucleotides, dendrimers, plasmids and phages (Freytag et al. 2007). These can be used for large scale production. Also, they have the advantage of possessing little or no host immunogenicity. And modified versions possess almost the same transfection efficiency or more than that of the viruses.
Although gene therapy can be used in the treatment of most genetic disease or disease arising from genetic alterations, the main use of gene therapy in medicine nowadays is in the treatment of cancers. Cancers arise as a result of mutation(s) in the genome of a particular cell line. The mutation in the cell’s DNA impairs the regulatory processes controlling cell growth, cell division or turnover so that the cell just continues to replicate endlessly. The most common cancer in men is prostate cancer and it affects the prostate glands. When the gene of the prostatic cells becomes altered, there is an uncontrolled proliferation of these cells and they begin to invade surrounding tissues, causing problems in other body systems. There are several reasons why prostate cancer is a very good candidate for gene therapy. Some of the factors that are responsible for this include the following: easy anatomical accessibility to the organ in the perineum, the natural history of the development of prostate cancer, and the wide knowledge base about the condition (Lu 2009). Research has been able to elucidate some regulatory genes and proteins controlling prostatic cell growth and division. One of these is the p53 gene (Michael et al. 2006). This gene is referred to as a cancer or tumour suppressor gene. Its main role is to serve as a policeman or checkpoint along the pathway of cell division. It becomes a policeman when it discovers that the cell’s DNA is damaged along the way, and hence disallows the cell from continuing in the cell cycle. But in cancers, this gene is destroyed such that cells with damaged genes still continue in the cell cycle and then continue to produce more damaged cells. Also, the p53 gene ensures that damaged cells are destroyed by a process known as apoptosis, but when the p53 gene itself is damaged, mutant cells continue to replicate and then start invading surrounding tissues. This is not to say, however, that p53 is the only tumour suppressor gene in existence. Over 30 tumour suppressor genes have been discovered with each of them having its own contribution to preventing cancers.
One of the main principles of gene therapy in prostate cancer is then therefore to enhance the function of p53 or to repair it when it is damaged. And in a lot of studies carried out on prostate cancer patients, it was discovered that p53 was mutated in several prostate cancer cell lines. Also, clinical trials have shown that replacement of the p53 gene can stifle further development of cancerous cells in the prostate (Freytag et al. 2007).
Apart from the p53 gene, some other genes have been implicated in prostate cancer. Another major one is the p16 gene which is lost in most locally invasive prostate cancers. Incorporation of vectors bearing this gene into the cancerous cells has been associated with reduction in the size of the tumour and a longer five-year survival period (Suzuki et al. 2007). Also, suppression of oncogenes is another principle in the treatment of prostate cancer with gene therapy. This can be achieved by the expression of antisense oligonucleotides or other protein enzymes that can cleave particular mRNA sequences such as ribozyme (Freytag et al. 2007).
Gene therapy offers several benefits to individuals undergoing the treatment (Bleijs, Haenen & Bergmans 2007). Studies have shown different cytopathic changes in the tumour after commencing the treatment. Some of the changes include the initiation of necrosis at various foci on the tumour, loss of nuclear details, and the observation of thick mononuclear infiltrates. The presence of cytotoxic T-cells and macrophages in the prostate of gene therapy-treated people implies an inflammatory response against the tumour. Although, like most treatment modalities particularly pharmacological therapy, gene therapy is not without its own side effects, but the long term effects far outweigh side effects. Possible risks associated with gene therapy include the occurrence of infections, when viruses used as vectors are injected into the wrong cell, causing mutations in the DNA or a malignancy straightaway; or when the new genes incorporated into a cell’s DNA are over expressed, resulting in excessive production of the initially absent or defective protein (Small et al. 2006). But when compared with other forms of cancer treatment, gene therapy has potentially very low toxicities.
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- Dr P. Ronald (Author), 2011, Gene Therapy and Prostate Cancer, Munich, GRIN Verlag, https://www.grin.com/document/368311