Gene Therapy Used In Severe Combined Immunodeficiency Diseases Biology Essay


Although it is still a fairly young technique, scientists have come a long way in developing what is present day gene therapy. Gene therapy was first conceived in the 1970's but it wasn't until the early 1990's that its pioneer experiments were first approved to be carried out. Today, newer techniques are advancing and continuing to change the ways we hope to correct inherited diseases by introducing genetic material into a person's somatic cells (Kohn, 2009).

Thus far one of the most prominent disorders that have been used in gene therapy is severe combined immunodeficiency disease (SCID). SCID is also more commonly known as the "Bubble Boy" disease and victims are highly susceptible to infectious diseases. In September 1990, a 4-year-old child with SCID became the first patient with a genetic disorder to be treated with gene therapy using a retroviral vector (Nienhuis 2008). SCID in this cause was caused by the lack of a functioning gene for adenosine deaminase (ADA), an enzyme that metabolizes the A nucleotide e of DNA (Gaspar 2009). The defect is particularly damaging for white blood cells such as B and T-lymphocytes. One method of treating ADA is transplantation of bone marrow, a tissue capable of making lymphocytes (Kohn 2009). Another yet more expensive method is the regular injection of the ADA protein. The ADA+ protein is a viable candidate for gene therapy because it seems to be the only one controlling the amount of ADA enzyme produced. The gene activity is regulated in a always way manner instead of a regulatory complex network like many other genes. There is also a better chance that giving the patients lymphocytes with a single working ADA+ gene would cure the disease (Aiuti 2009). Further experiments are still being done and patients infused with transduced retroviral vectors in their bone marrow cells appear to show progress.

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An increasing understanding of the retroviral life cycle made possible by molecular biologic techniques led to the organization of the retroviral genome. With increasing knowledge about the mechanisms in gene regulation, it aided in the development of vectors capable of gene transfer into cells. Gene therapies commonly use the transgene which is simply added to the host cell without removing any part of the host's genomic DNA. This is aided by the use of viruses that can insert their DNA into the chromosomal DNA of their host cells. Scientists can benefit from the ability of viruses to rupture the plasma membrane of the host cells and insert their viral genes into the host's (Aiuti 2009).

Retroviruses use RNA as their genetic material and many are used in gene therapy. They reverse transcribe their RNA genome into DNA once they are in the host cell's cytoplasm. It inserts itself into the chromosomal DNA after the DNA transcript enters the host cell's nucleus. However, this step occurs randomly and is not predictable and may affect nearby neighboring genes. Such instances include deregulation of nearby genes that control the cell cycle or tumorous growth. Some examples of retroviruses include the lentiviruses, HIV virus, and murine leukemia virus (MLV). MLV virus can be used for assisted suicide of tumors because it can have access to chromatin only in dividing cells. In contrast, the adenovirus which also is used in gene therapy does not insert itself into the host genome and avoids such hazards of random insertion. However it also contains its own problems and has been seen to produce allergic reactions in humans. Patients show different levels of symptoms and it varies from one to the next. It is difficult to find a dosage that are safe for patients but also elicit the same response and results that is effective (Calvo 2007).

A normal ADA+ gene was inserted into a vector of the first two cases of the two girls with SCID made from MLV retrovirus. Lymphocytes prepared from each of their blood was used ex vivo with the MLV vector carrying the ADA+. The lymphocytes were returned back to the girls' bloodstream after time was given for infection and testing. The first patient, Ashanthi de Silva, showed improvement in her treatment after beginning at the age of four. More than half of her circulating lymphocytes contained the transgene and produced ADA even three years later (Coutts 1994). She was able to lead a relatively normal and active life. However, the second patient did not see such successful results and developed an immune response. Less than one percent of her circulating lymphocytes contained the ADA gene and she was not able to produce it on her own. Such results pushed scientists to believe that perhaps Ashanthi's may have included stem cells. They expressed both vector and ADA+ genes past the typical lifetime of differentiated lymphocytes. This has lead to the use of gene therapies consisting of tissues that would contain blood stem cells, which can be found in umbilical cord blood or bone marrow (Nienhuis 2008).

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A clinical trial began in 1990 in France for SCID caused by a defective X-linked gene treated two children of ages eight months and eleven months. Once again, bone marrow cells from the patients were infected with retroviral vectors containing a function SCID-XI gene ex vivo. The cells were then transferred back into the patients afterwards. Improvement was seen and their lymphocyte development showed much improvement and even became near normal. Nine out of the ten children eventually were successfully treated. Other trials also displayed similar successful results. But amidst the success, some of the first fatal results occurred. In the trial in France, three children developed T-cell leukemia and one of them died. This was due to the fact that the retrovirus had inserted into the regulatory region of a gene which promoted cell division, leading to deregulated growth (Howe 2008).

The traumatic death of another patient in 2000 for gene therapy also left scientists wondering the implications and risks of gene therapies. These risks will always be present in gene therapy due to the unpredictable nature of many viral vectors but it is also a sign of hope for others. Gene therapy for some is the only hope for some patients who have no other options or treatments that may help them. But at the same time, much more is needed to be known about such viral vectors and their reactions to ensure that no other patients will be harmed. Currently, most clinical trials have been reduced in number and each is very cautiously carried out. The patients are very restricted in their criteria and regulations are very strict. Only through this way can advances in gene therapy carried out but the safety and wellbeing of the patients is also taken into consideration. Despite complications that have occurred in gene therapy studies, many successful outcomes have stemmed from it and continue to help many. The successful progress of gene therapy also has the ability to have "significant economic benefits" with the rising costs of medical care for severe or chronic conditions (Nienhuis 2008).