Gene Therapy, Safety Concerns and Improving Safety Methods - Essay Example

?Gene Therapy, Safety Concerns and Improving Safety Methods Gene therapy is a method of treating various acquired and genetic diseases with genes. This is an experimental technique and is done by inserting genetic material into the patient’s cells. In this form of treatment, the diseases are either treated or prevented by replacing abnormal gene, or by introducing the absent gene or by supplementing the defective gene (Genetics Home Reference, 2008). The genes thus introduced exert their benefits by either compensating for the abnormal genes or by producing beneficial protein or by supplementing the abnormal gene (Hecht, 2004). The first gene therapy clinical trial started in 1990 (Verma and Weitzman, 2005). Currently, research is going on for gene therapy by various approaches in different parts of the world for various diseases like combined immuno-deficiencies, hemophilia, Parkinson's disease, cancer and even HIV (Verma and Weitzman, 2005). Though gene therapy has been under research for the past 2 decades, no single gene therapy has been approve for clinical use. The main reason for this is safety concerns pertaining to gene therapy trials and treatment. In this essay, various strategies to increase the safety of gene therapy will be discussed through review of suitable literature. Safety issues related to gene therapy are mainly related to the methods employed in gene therapy. There are basically 2 methods of gene therapy and they are ex-vivo therapy and in-vivo therapy. In ex-vivo therapy, gene delivery is done in cells after being removed from the body (Hecht, 2004). The cells used thus are basically grown in the laboratory. The cells are than modified outside the body and then transplanted back into the body. In some research trials, cells from blood or born marrow are taken out and cultured in a laboratory. Thereafter, the cells are exposed to the virus with the desired gene. The virus infects the cells and transfers the therapeutic genetic material into the nucleus of the cells. After this, the cells are injected into the patient’s body by vein. In in vivo therapy, gene delivery is done in the cells that are still in the body. The simplest method of introducing therapeutic genetic material into the cells is direct introduction into target cells. However, this method is not practical because it can be used only with certain tissues and requires large amounts of DNA. Other methods are there wherein the genes are delivered into cells by vectors like viruses or bacteria, by electroporation or tiny synthetic "envelopes" of fat molecules (Hecht, 2004). Of these, the most commonly used vector is virus. Vector is the carrier of the gene. Viruses are used as vectors to deliver genetic material to the nucleus of the cell that contains its DNA. The natural ability of a virus to enter a cell is used for this purpose. The viruses used for gene therapy are retrovirus, adenovirus, adeno-associated virus and herpes simplex virus (Genetics Home Reference, 2008). While preparing the vectors for gene therapy, the DNA coding for a part or whole of the normal genes of the virus to be used as a carrier is removed and replaced with the treatment gene. The carriers are engineered in such a way that there ability to enter the cells is not lost but they cannot reproduce. Genes delivered by tiny synthetic "envelopes" of fat molecules enter the cell by cell membrane which has very high concentration of fat molecules. In electroporation, the genes are delivered into the cells by creating tiny openings in the cell membrane. This is done by using a bionic chip. The chip contains a single living cell embedded in a tiny silicon circuit (Hecht, 2004). Another method of gene therapy is where the therapeutic gene gets inside the target cell by chemically linking the DNA to a molecule that will bind to special cell receptors. After binding to these receptors, the DNA is engulfed by the cell membrane and passed into the interior of the target cell. However, this is less effective than the other methods (Genetics Home Reference, 2008). The genetic material can be delivered by different routes. The specific route is determined by the disease. Gene therapy for cystic fibrosis is administered by inhalation. In hemophilia and cancer treatment, the gene is directly injected into the tumor (Hecht, 2004). Viral vectors can introduce toxicity, immune and inflammatory responses. Also, though the viruses are engineered to be innocuous, there is always a fear that they may cause disease (Hecht, 2004). Immunogenecity is an important factor with regard to safety of the patient subjected to gene therapy trial. The immunogenecity is that of the vector and it is derived from the proteins of the virus and the capability of the viruses to infect macrophages and dendritic cells. Such an immune response can result in elimination of the transduced cells and also the vector. The potency and dose are very important aspects for good outcomes in gene therapy and these are basically linked to the production process and also the purification process (Raty et al, 2008). These processes maximize the infective virus and decrease the number of defective viruses or empty viral particles. Using administration methods to increase the concentration of the virus locally helps in decreasing the side effects and also aids in lowering the amount of total dose that is administered into the patient. In the ex-vivo approach, cells of the patient that are outside the body like skin can be used for transduction for augmentation of the grafting of the tissue and also for providing therapeutic protein secretion. These methods help in limiting the exposure to the patient to vectors of gene delivery, thus increasing safety aspects. These methods are however, laborious. Another method of decreasing the amount of dose administered to the person is by combining lipoproteins of low density with avidin (Raty et al, 2008). In this method, substances that are bitinylated are captured to the cells from the circulation, thus effectively increasing the drug concentration locally. This helps in reducing the side effects by limiting the amount of drug concentration in other tissues. Certain tissue specific promoters when used with gene therapy vectors along with regulatable promoters can help in decreasing the amount of vectors exposed to the body. Another startegy is to delete the replication genes in the vector, mostly adenovirus, so that the viruses are gutless. Currently third generation vectors are being used which are much safer. Improvement in chromatographic methods have decreased the purification of viruses and also the delivery of reservoirs like silicon collars or collagen collars which decrease systemic leakage of viruses along with tissue specific promoters. Imaging the biodistribution of particles of virus can help in gene therapy specificity, thus improving safety aspects (Raty et al, 2008). To summarize and conclude, introduction of genetic material into the cells for therapeutic purposes is known as gene therapy. This mode of treatment is useful for diseases with gene absence, mutation or insufficiency. However this is still in experimental stage. Gene therapy offers hope to those with incurable genetic disorders, but is fraught with several challenges and side effects. One of the safety methods that has been adopted is deletion of replication genes E1 and E3 of adenovirus, thus making the adenoviruses gutless. In lentiviral vectors, currently third generation self-inactivating vectors are being used for gene therapy. This is subsequent to evolution from first generation to third generation vectors. Improvement in the chromatographic methods have enhanced the purification of viruses and also the delivery reservoirs. Good examples of such purification methods are silicone bars and collagen. These are especially useful for cardiovascular gene transfer and they decrease systemic leakage of viruses used for gene therapy. Other strategies which can reduce harm due to gene therapy viruses are using of tissue specific promoters and also imaging of the viral biodistribution. References Hecht, F. (2004). Gene Therapy - The Future Is Here! MedicineNet.com. Retrieved July 15th, 2011 from http://www.medicinenet.com/script/main/art.asp?articlekey=12662 Raty, J.K., Lesch, H.P., Wirth, T., Yla-Hertuala, S. (2008). Improving Safety of Gene Therapy. Current Drug Safety, 3, 46-53. Genetics Home Reference (2008). What is Gene Therapy. Retrieved on 15th July, 2011 from http://ghr.nlm.nih.gov/handbook/therapy/genetherapy Verma, I.M., Weitzman, M.D. (2005). Gene therapy: twenty-first century medicine. Annu Rev Biochem, 74, 711-38. Read More