Introduction of modified genes into the human genome to compensate for aberrant, i.e. nonfunctional, mutated or genes which cause disease is called gene therapy. Theoretically, a normal allele of the defective gene can be inserted into the somatic cells of the tissue affected by the disorder. Gene therapy is the technique which is trying to put this theory to practice. Unlike the usual medical practices, gene therapy targets the cause of the disease rather than the symptoms. All of us carry mutated genes which are many a times recessive, but rarely dominant. About one in ten people have, or will develop at some later stage, an inherited genetic disorder, and approximately 2,800 specific conditions are known to be caused by mutations in just one of the patient’s genes. The most beneficial aspect of gene therapy is that it can wipe out genetic disorder before they begin and eliminate suffering for future generations. In this technique, an abnormal gene is swapped for a normal gene through homologous recombination or the abnormal gene is repaired through selective reverse mutation, which brings back a gene to its normal function. Gene therapy also involves the regulation or protein production of a particular gene. These practices can be administered in two ways. One is germline therapy which deals with reproductive or gamete cells and the other is somatic cell therapy which deals with the non-reproductive cells of the body.
Gene therapy works by inserting the therapeutic gene into a vector which carries the gene to its target site. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. This capability of viruses is made use of by manipulating the virus genome to remove disease .
Besides virus mediated gene delivery systems, there are several non viral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only in certain tissues and requires large amounts of DNA. Another non viral approach involves the creation of an artificial lipid sphere (liposome) with an aqueous core, which carries the therapeutic DNA, which is capable of passing the DNA through the target cell’s membrane. Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule which carries it to the target site; although this delivery system tends to be less effective than other options.
The first gene therapy trial for SCID (Severe Combined Immunodeficiency Syndrome) began in 1990. But the clinical results from this and succeeding studies during the 90s could not convincingly demonstrate the effectiveness of the treatment. In another trial that started in 2000, ten young children with SCID were treated by the same procedure. Nine of these patients showed significant improvement after two years, the first indisputable success of gene therapy. However, two of the patients subsequently developed leukemia, a type of blood cancer. It was discovered that in both these cases the retro viral vector used to carry the normal allele into the bone marrow cells had inserted a gene involved in the proliferation of blood cells, causing leukemia. Since then FDA (Food and Drug Administration) has not approved any human gene therapy for sale, though active research in this field continues with an appreciable degree of response.
Despite some failures, gene therapy proved to be a successful treatment for many rare and incurable diseases. The gene therapy was tested for a type of inherited blindness, the procedure helped in restoring vision of dogs without any side effects. The results,
published in the New England Journal of Medicine (28 April 2008), showed that the experimental treatment by gene therapy is safe and can improve sight. Another xperiment was done by researchers at the National Cancer Institute (NCI) who re-engineered lymphocytes, to target and attack cancer cells in patients with advanced metastatic melanoma. Also, gene therapy was effectively used to treat two adult patients for a disease affecting non lymphocytic white blood cells called myeloid cells. The study was the first to show that myeloid disorders such as acute myeloid leukemia can be cured by gene therapy. There are many limiting factors of gene therapy such as the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long lived and stable. Moreover, problems with integrating therapeutic DNA into the genome prevent gene therapy from achieving any long term benefits. Also, gene therapy can be effective only in proliferating cells, consequently non-dividing cells such as neurons cannot benefit from this technique. In gene therapy viral vectors are used to carry genes into the body, they might alter more than the intended cells and present a variety of potential problems to the patient such as toxicity, immune and inflammatory responses. Another major problem arises from the fact that we have no means to regulate the protein expression of induced genes. As a result the therapeutic gene may be over-expressed to the level of toxicity. The site and the chromosome where the gene is inserted also remains uncertain, which adds to the side effects, especially since the locus of a gene can greatly effect its functioning.
Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer’s disease, arthritis, and diabetes, are
caused by the combined effects of alterations in many genes. Multi gene or multi-factorial disorders such as these would be especially difficult to treat effectively by using gene therapy.Scientists use animal testing and take other precautions to assess and avoid these risks.These safety measures have been successful to the extent that these potential problems have not occurred in any of the human gene therapy trials performed to date. However,complete elimination of these problems remains uncertain. In addition to technical challenges, gene therapy raises difficult ethical questions. Critics suggest that tampering with human genes in any way will inevitably lead to the practice of eugenics, a deliberate effort to control the genetic makeup of the human population. Germ line therapy which potentially alters the genetic makeup of gametes or germ cells, involves too much uncertainty, risk, and the long term effects are unknown. Changes made in the germ lines could persist in the population for a long time. In a way, this could be thought of as interfering with the natural phenomenon of evolution. The elimination of unwanted genes which may be an unavoidable consequence of the success of gene therapy, could prove to be detrimental in the long run. Genetic variation is necessary for the survival of a species as environmental conditions change with time. Genes that are damaging under some conditions may be advantageous under other conditions .
Gene therapy may be the best weapon medicine has ever brought to the fight against birth defects and many other health problems. As research moves forward, gene therapy may advance to the extent that it might prevent or ease hundreds of devastating
conditions, including types of mental retardation, congenital heart disorders, blood diseases and many others. But the paramount concern is the risk of the procedure. Finding the precise location of the defected gene is still under research. Any
miscalculation could cause a risk of a new disease such as cancer to form.
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