The theory of recombinant DNA technology was enhanced and used in scientific res

Question

The theory of recombinant DNA technology was enhanced and used in scientific research and now has practical medical applications in Gene Therapy. Within the last two decades, there have been major advances in treating genetic diseases that were one thought to be incurable. Discuss a current article where recombinant DNA technology, like Gene Therapy, has been used to treat a genetic disorder like SCIDS (Severe Combined Immunodeficiency Syndrome, aka "The Boy in the Bubble Syndrome"), Diabetes, or Cystic Fibrosis. Discuss the following issues:

* How has the use of recombinant DNA technology added to the treatment of the disorder?
* How has the treatment affected the long-term quality of life and long-term outlook of people with the disorder?
* Is more research necessary?


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Thank you!

Explanation / Answer

What is gene therapy? Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result. Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes: * A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common. * An abnormal gene could be swapped for a normal gene through homologous recombination. * The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function. * The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered. How does gene therapy work? In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. 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. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causing genes and insert therapeutic genes. Target cells such as the patient's liver or lung cells are infected with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state. See a diagram depicting this process. Some of the different types of viruses used as gene therapy vectors: * Retroviruses - A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus. * Adenoviruses - A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus. * Adeno-associated viruses - A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19. * Herpes simplex viruses - A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores. Besides virus-mediated gene-delivery systems, there are several nonviral 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 with certain tissues and requires large amounts of DNA. Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core. This liposome, which carries the therapeutic DNA, 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 that will bind to special cell receptors. Once bound to these receptors, the therapeutic DNA constructs are engulfed by the cell membrane and passed into the interior of the target cell. This delivery system tends to be less effective than other options. Researchers also are experimenting with introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autonomously alongside the standard 46 --not affecting their workings or causing any mutations. It would be a large vector capable of carrying substantial amounts of genetic code, and scientists anticipate that, because of its construction and autonomy, the body's immune systems would not attack it. A problem with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell. What is the current status of gene therapy research? The Food and Drug Administration (FDA) has not yet approved any human gene therapy product for sale. Current gene therapy is experimental and has not proven very successful in clinical trials. Little progress has been made since the first gene therapy clinical trial began in 1990. In 1999, gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures 4 days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier. Another major blow came in January 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome." FDA's Biological Response Modifiers Advisory Committee (BRMAC) met at the end of February 2003 to discuss possible measures that could allow a number of retroviral gene therapy trials for treatment of life-threatening diseases to proceed with appropriate safeguards. In April of 2003 the FDA eased the ban on gene therapy trials using retroviral vectors in blood stem cells. What is Human SCID? Lymphocytes are white blood cells present in the immune system of vertebrates. T cells and B cells are the two types of lymphocytes. The immune system protects our body from infections. The T (thymus) cells are responsible for cell-mediated immunity i.e. they boost other immune cells to oppose foreign substances. B cells undertake the humoral immunity. They produce anti-bodies which fight with the antigens present in the humor (body fluid), hence the name humoral immunity. Defects in the T and B cells result in severe combined immunodeficiency syndrome. SCID is a genetic disorder. There are two major types of SCID * XSCID: In this type of SCID, the gene that is present on the X chromosome, called IL2RG, is mutated. * ADA SCID: ADA (Adenosine Deaminase) is an important enzyme which helps in producing new DNA. In ADA SCID, the gene that encodes ADA is mutated. A patient of SCID is susceptible to all kinds of infection, due to the improper functioning of the immune system. SCID is detected in new born babies. 1 among 80,000 live births are found to have SCID. However, the babies suffering from SCID do not usually survive long. What is Gene Therapy? Gene therapy is a recent development in genetic and cell-based biotechnology in which genes are inserted in cells or tissues to deal with a genetic or hereditary disorder. Gene therapy has been successful in preventing and curing many genetic disorders. It includes replacement of the defective gene with a new gene. Gene Therapy for Human Severe Combined Immunodeficiency Disease In gene therapy for human SCID, the mutated gene present in X chromosome (IL2RG) or the mutated gene that encodes ADA is replaced by normal genes. The replacement makes the immune system work efficiently. In 1990, NIH (National Institutes of Health) was permitted to implement human gene therapy for the first time. A four year old girl, Ashanti DeSilva, suffering from ADA SCID was the first one to be treated with gene therapy for human SCID. Some T cells were removed from her body and a normal copy of ADA gene was inserted into these T cells. These T cells were again injected into her body. The repeated treatments resulted in normalization of the number of T cells. She had a normal immunity, but continued receiving replacement gene therapy of T cells. This experiment could not prove that gene therapy could completely cure ADA SCID, but it did prove that ADA SCID can be cured, if the proper gene was inserted into sufficient number of T cells. In France, however, it was found that children treated for XSCID with gene therapy, developed leukemia. The method for insertion of corrected genes triggered an oncogene (cancer causing gene), which resulted in leukemia. As a result of this, gene therapy treatments for SCID were discontinued for a long period of time. Researches are conducted to treat XSCID with gene therapy without triggering an oncogene. No cases of leukemia are seen in experiments carried out for the treatment of ADA SCID through gene therapy. Other than gene therapy, bone marrow transplant and 'Bubble Boy' are some other treatments for SCID. Bone marrow transplant is the most effective. However, a proper 'bone marrow match' is necessary for transplantation. If a match is not found, the SCID cannot be treated. In Bubble boy treatment, the baby is kept in a bubble-like structure where it can be kept isolated from infections. Gene therapy, however, is a more efficient form of treatment in comparison to Bubble Boy. Moreover, as it is difficult to procure a 'match' in case of a bone marrow transplant, gene therapy can prove to be more beneficial. So far, immune systems of 17 children suffering from either XSCID or ADA SCID have been restored by gene therapy. Although gene therapy of human severe combined immunodeficiency (SCID) has its limitations, it has proved to be an effective form of treatment.

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