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ADVANCE MICROBIAL GENETICS
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INTRODUCTION
Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. It derives its name from the idea that DNA can be used to supplement or alter genes within an individual's cells as a therapy to treat disease. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene in order to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within a "vector", which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease (Sheridan, 2011).
Gene therapy was first conceptualized in 1972, with the authors urging caution before commencing gene therapy studies in humans (Friedmann et al., 1972) The first FDA-approved gene therapy experiment in the United States occurred in 1990, when Ashanti Desilva was treated for ADA-SCID Since then, over 1,700 clinical trials have been conducted using a number of techniques for gene therapy (Sheridan, 2011).
Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes in 2006-2011 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease Leber's congenital amaurosis (Maguire et al., 2007), X-linked SCID, ADA-SCID, adrenoleukodystrophy, chronic myelogenous leukemia (CML) and Parkinson's disease (Fischer et al., 2010; Ferrua et al.2010; LeWitt et al., 2011). These recent clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field (Kohn, 2009).
Examples of Gene therapy
This new therapy appears to work quite well in the laboratory setting or theoretically in some scientist's mind, but it still had not been proven in a human subject. The first human to receive gene therapy treatment was a 4 year old girl with severe immune-deficiency disease. This disease is caused by a faulty gene that fails to produce a vital enzyme. In the therapy procedure, they extracted some of the girl's white blood cells. Then, they exposed them to a genetically engineered virus that had lost its virulence but still carried normal versions of the gene that was not functioning correctly in the girl. The virus invaded the white blood cells, and then these cells were transfused back into the girl. Once back inside the girl's bloodstream, the cells began producing the proper enzyme. Although the girl still needs follow-up treatments, she now leads a relatively normal life following the gene therapy. This is one of the success stories of gene therapy (Sheridan, 2011).
Types of gene therapy
Somatic gene therapy
In somatic gene therapy, the therapeutic genes are transferred into the somatic cells, or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations. Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual (Sheridan, 2011).
Germ line gene therapy
In germ line gene therapy, Germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are integrated into their genomes. This would allow the therapy to be heritable and passed on to later generations. Although this should, in theory, be highly effective in counteracting genetic disorders and hereditary diseases, many jurisdictions prohibit this for application in human beings, at least for the present, for a variety of technical and ethical reasons (Strachnan et al., 2004).
Vectors in gene therapy
Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by a numbers of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods) (Gardlik et al., 2005)
Viruses
All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA. A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex virus, vaccinia, pox virus, and adeno-associated virus (Sheridan, 2011).
Some of the problems of gene therapy include:
• Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
• Immune response – Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
• Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient: toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
Preventive gene therapy
Preventive gene therapy is the repair of a gene with a mutation associated with a progressive disease, prior to the expression of a medical condition, in order to prevent that expression. There are a number of considerations:
• It is hard to get U.S. FDA approval to treat a pre-symptomatic condition because it is hard to predict the complications that may arise, so it is hard to give a risk/benefit analysis. This is an obstacle to long-term therapies.
• It is easier to gain approval for short-term therapies to treat expressed conditions rather than prevent them.
• It is not known whether the repair of a mutation will help to treat a condition which has already progressed beyond the initial consequences of that mutation (Mae-Wan Ho, 2005).
Disadvantages of Gene Therapy
The basis of gene therapy is find a gene that is not functioning right and to insert a healthy portion into that gene. To find these genes, scientists must perform genetic tests or genetic screening to see if the gene that causes for example, cystic fibrosis, is present. This genetic testing is producing much controversy and raising many ethical and legal problems. Many believe that this is an invasion of privacy. They believe that if prenatal tests are performed that these could lead to an increase in the number of abortions. Many people that hear a positive test for a disease are now are faced with a dilemma. That dilemma is in finding adequate insurance to cover the treatments, which could be gene therapy, or living out their lives knowing that they carry a gene for a disease. This positive test has placed them in a high risk group that they may have not been in if they had not been tested. This high risk tag makes insurance coverage almost impossible to find. The insurance that will cover them may be extremely expensive. So, choosing to have the test may be a question of whether they think their current insurance will cover them or not. Many young couples may find out that they are carriers of a disease, and now must decide if they want to have a child that could be born with a genetic disease. Still another problem is regulation of the uses of gene therapy. Our society is obsessed with the idea of youth and beauty. If scientists could identify the gene that contributes to youth or beauty, then the technique of gene therapy could be monopolized by the cosmetic industry to enhance beauty or to "turn back the clock." The problem with this is whether baldness, height, or beauty should be enough of a reason to require gene therapy. Federal regulation will have to come into play in deciding whether a big nose is as important of a genetic problem as cystic fibrosis and which requires gene therapy (Broody, 1993).
Advantages of Gene Therapy
The advantages of gene therapy far outweigh the disadvantages. The advantage of the technique is to give someone that is born with a genetic disease or who develops cancer the chance at a normal life. I think this is an advantage that far outweighs any of the disadvantages that have been presented against gene therapy. Giving someone a chance at a normal life should be enough for many of the people that oppose this technique to change their minds. I believe the reason that these people are opposed to gene therapy is because they see it as something foreign and scary. The reason people are scared is because they do not understand the technique. I think if scientists educate our society, many people would change their minds. I believe that if the people that oppose this technique were ever faced with cancer or a child born with a genetic disease, they would change their views. These sceptics would choose gene therapy, especially if it would save a loved one's life. In the coming future, gene therapy will play an important part in many people's lives. Giving an advantage to someone who has born with a genetic disease by replacing non-functional gene with a functional one may give someone a chance of normal life. A cancer patient can also get advantage of this technique by insertion of genetically altered vectors into human genome (Hor, 2004)
The Pros and Cons of Gene Therapy
The ethics that surround the issue of gene therapy are very overwhelming. Some people think that we will get burnt trying to play God while others think this is a great advancement for mankind. One reason for unacceptance may be that gene therapy may be used for the enhancement or modification of human capabilities. If this were feasible, the standards of a normal human being would be changed. Even if some small countries experimented with gene therapy, could they develop unstoppable armies? If gene therapy was done to a certain extent could it alter the human gene pool for good? And also would this form of treatment be a luxury only for the rich which could very well make the rich, richer and make the poor, poorer. For just these reasons an d theories, all gene therapy experiments must receive approval from the Recombinant DNA Advisory Committee (RAC) and the National Institutes of Health, (NIH). After approval by these committees the trials must also receive approval from the U.S. Food and Drug Administration (National Cancer Institute, 1993).