The Pros And Cons Of Gene Therapy
Gene therapy is an experimental treatment, which is used to replace mutated, improperly functioning genes with regular DNA. There are several gene therapy methods, most of which involve using a vector to transport the corrected gene into targeted cells. Retroviruses, adenoviruses, adeno associated viruses and liposomes are commonly used as vectors. Naked DNA (DNA without a vector) has also been used in gene therapy. Recently, gene therapy has been used as a treatment for deadly genetic conditions such as cystic fibrosis. Even though gene therapy has a promising future, it has major disadvantages; including vector inefficiency, incorrect vector implantation and the possibility for a dangerous immune system reaction. In addition to these disadvantages,
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there are genetic and environmental prerequisites that must be met prior to attempting gene therapy. CF is an autosomal recessive disorder which is caused by the deletion of 3 codons on chromosome 7. This mutation, known as delta F508, results in a lack of chloride ion secretion, due to a lack of the amino acid phenylalanine. Ultimately, delta F508 results in thickened mucus in the respiratory and digestive systems. The disease is prevalent in western society; 1 in 2500 people have the disease and an estimated 1 in 25 people are carriers. Symptoms of cystic fibrosis include shortness of breath, high risk of lung infection, malnourishment and constipation. Currently, CF is incurable, however, the symptoms can be improved with inhalers, nebulisers, laxatives and antibiotics. In the future, it is very likely that gene therapy will be used to cure genetic disorders such as CF.
In gene therapy, the corrected gene needs to target specific cells. For example, the affected cells in cystic fibrosis are the epithelial cells of the respiratory and digestive systems. If the corrected copy of the gene isn't delivered to the correct cell, the treatment will be ineffective and/or dangerous. In gene therapy, a vector is often used to transport the gene into the cell. Without a vector, mutated cells cannot be targeted, which means the treatment will be ineffective. Since the 1980’s, scientists have experimented with the use of viral vectors. These include adenoviruses, adeno associated viruses and retroviruses. Although these viruses can target specific cells more effectively than naked DNA, they are often ineffective and dangerous. In 1984, scientists began using retroviruses as vectors. These viruses are ineffective as they only affect dividing cells. This means that organ cells (eg.epitheleal lung cells) that divide infrequently would be unable enough of the corrected gene. Adenoviruses have also been used in gene therapy. They can target specific cells, however, they are likely to trigger dangerous reactions in the patient. The safest viral vectors are adeno associated viruses. These viruses permanently integrate the gene into the cell's DNA and are unlikely to trigger an immune response compared to other viral vectors. However, these viruses can only fit small amounts of DNA. Scientists have also experimented with the use of non-viral vectors and hybrid vectors. Liposomes are phospholipid spheres which are used to transport medicines to cells. Scientists have placed functional genes in liposomes to treat genetic mutations. However, liposomes are ineffective, due to the fact that they can be toxic and do not target specific cells. All vectors used in gene therapy have disadvantages. This is why scientists are currently combining viral and non-viral vector methods. Virosomes are liposomes covered with viral proteins. They can be used to target specific cells, but are less likely to cause an immune response. In future, researchers will gravitate towards the use of hybrid and non-viral vectors in gene therapy; as they are safe and efficient in targeting cells compared to viral vectors.
A major disadvantage of gene therapy is that there is the potential for a dangerous immune response. Naturally, the immune system fights foreign pathogens. This function is crucial for health, However, it can cause dangerous side effects during gene therapy. As mentioned previously, gene therapy patient Jesse Gelsinger died from multiple organ failure, after treatment for an X-linked liver disease. Since Gelsinger's death in 1999, gene therapy researchers have focused on using the lowest effective dose of the corrected DNA possible. Immunosuppressants have also been used to eliminate the risk of immune response. However, immunosuppressants can have serious side effects such as severe infection and uncontrollable bleeding. In cystic fibrosis patients, the use of immunosuppressants would likely result in death due to lung infection. One way to limit immune response without increasing infection risk is by Inserting the corrected gene into the target cells outside of the body. Normally, vectors are injected, swallowed or inhaled by patients depending on the location of the target cells. This method of gene therapy is called in-vivo because the treatment occurs inside the body. The ex vivo method of gene therapy involves harvesting target cells and growing them in a petri dish via tissue culture. By using the ex vivo method, a dangerous immune system response cannot occur and scientists can check that the gene has been successfully implanted into the genome. In cystic fibrosis, the epithelial lung cells are harvested via transthoracic lung biopsy; a procedure in which a small incision is made and a needle is injected into the lung. Gene therapy is dangerous, due to the likelihood of a negative immune response. However, scientists are continually learning how to improve this technology and how to balance its effectiveness with safety. In future, ex vivo gene therapy will become more common as it eliminates the chance of an immune system response.
Another disadvantage of gene therapy is the fact that corrected gene copies can integrate into the genome incorrectly. For a gene therapy treatment to work, the corrected gene must implant itself into the genome. Certain viruses such as adenoviruses do not integrate into the genome permanently and therefore the corrected copy of the diseased gene is removed within a few weeks. Retroviruses, on the other hand, integrate into the cell's genome permanently. However, retroviruses have been found to integrate into random parts of the genome. 1999 and 2006, researchers performed gene therapy on 5 children with a genetic immunodeficiency, using retroviruses as vectors. By 2006, all 5 of these children had developed leukaemia as a result of the vector implanting into an incorrect part of the genome. When the corrected gene integrated into the genome, a frame shift occured due to insertional mutagenesis. This meant that existing gene was disrupted, creating an oncogene (cancer-causing gene) known as LMO2. Adeno associated viruses and non-viral vectors do not integrate into random parts of the genome. Therefore, it is likely that scientists will abandon the use of retroviruses and adenoviruses for gene therapy in favour of adeno associated viruses and non-viral vectors.
It is important to note that gene therapy can only be considered when certain biological prerequisites have been met. Firstly, gene therapy only works when used as a treatment for monogenic (single gene) mutations. Many genetic conditions such as heart disease, autism, schizophrenia, diabetes and high blood pressure involve multiple point mutations on different genes. Secondly, gene therapy will not work if the disease has multiple causes. In some genetic conditions, such as autism; symptoms are caused by a complex web of point mutations. It is difficult to figure out which gene to target if the disease can be caused by an unknown variety of mutations. Thirdly, gene therapy will not be effective if environmental factors are present. Sometimes a genetic mutation is asymptomatic until certain environmental conditions are met. Finally, many genetic disorders are caused by larger scale chromosome mutations (duplications, inversions, aneuploidies etc). At present, scientists cannot treat these disorders. At present, gene therapy can only treat a small number of simple genetic mutations. In the near future, it is likely that scientists will improve current treatments and develop new gene therapy methods such as germline therapy as well as therapies that target large-scale chromosome mutations. Germline gene therapy involves using vectors to correct genetic abnormalities in gametes. Scientists have theorised that it would be effective and that the patient would be disease free for life. Researchers are currently experimenting with the use of genes for chromosome silencing. The XIST gene is found on the X chromosome. Researchers have found that the XIST gene can be harvested and inserted into other chromosomes with a vector, silencing the chromosome's activity. In future, this method could be used to turn off extra chromosomes in cells. However, this therapy would need to target multiple cells and at present, this cannot be done.
Gene therapy is a rapidly developing technology which aims to replace faulty genes with properly functioning copies to cure disease.
At present, there are major disadvantages to gene therapy. Firstly, it is difficult to target specific cells. However, researchers are continually developing more efficient vectors such as virosomes. Secondly, gene therapy can cause dangerous immune responses, as seen in the case of Jesse Gelsinger. However, researchers have begun to use vectors that don't cause an immune response; such as adeno associated viruses, virosomes and liposomes. Scientists have also harvested cells and performed gene therapy outside the body (ex vivo). This method of gene therapy does not cause an immune response and scientists can check whether or not the functional gene has been implanted into the genome. In future, it is likely that ex vivo gene therapy will become more common, as it is safer than in Vivo gene therapy. Thirdly, for gene therapy to succeed, the functional gene must integrate into the genome, in the right location (on the end of a chromosome). vectors such as the adenovirus do not integrate into the genome permanently; and retroviruses implant into random parts of the genome, causing frameshift mutations (as seen in the gene therapy-leukemia incident). Scientists are continually investigating the use of safer vectors, such as adeno associated viruses, liposomes and virosomes. Finally, it is important to note that gene therapy currently has limited uses. Disorders that involve multiple genes, chromosome mutations and/or environmental factors cannot be treated with gene therapy. In light of the aforementioned evidence, it is apparent that gene therapy is currently dangerous and ineffective. However, gene therapy is an experimental technology which has only been trialled in humans since 1990. Therefore, it is too early to rule out the use of gene therapy for genetic conditions such as
CF.
there are genetic and environmental prerequisites that must be met prior to attempting gene therapy. CF is an autosomal recessive disorder which is caused by the deletion of 3 codons on chromosome 7. This mutation, known as delta F508, results in a lack of chloride ion secretion, due to a lack of the amino acid phenylalanine. Ultimately, delta F508 results in thickened mucus in the respiratory and digestive systems. The disease is prevalent in western society; 1 in 2500 people have the disease and an estimated 1 in 25 people are carriers. Symptoms of cystic fibrosis include shortness of breath, high risk of lung infection, malnourishment and constipation. Currently, CF is incurable, however, the symptoms can be improved with inhalers, nebulisers, laxatives and antibiotics. In the future, it is very likely that gene therapy will be used to cure genetic disorders such as CF.
In gene therapy, the corrected gene needs to target specific cells. For example, the affected cells in cystic fibrosis are the epithelial cells of the respiratory and digestive systems. If the corrected copy of the gene isn't delivered to the correct cell, the treatment will be ineffective and/or dangerous. In gene therapy, a vector is often used to transport the gene into the cell. Without a vector, mutated cells cannot be targeted, which means the treatment will be ineffective. Since the 1980’s, scientists have experimented with the use of viral vectors. These include adenoviruses, adeno associated viruses and retroviruses. Although these viruses can target specific cells more effectively than naked DNA, they are often ineffective and dangerous. In 1984, scientists began using retroviruses as vectors. These viruses are ineffective as they only affect dividing cells. This means that organ cells (eg.epitheleal lung cells) that divide infrequently would be unable enough of the corrected gene. Adenoviruses have also been used in gene therapy. They can target specific cells, however, they are likely to trigger dangerous reactions in the patient. The safest viral vectors are adeno associated viruses. These viruses permanently integrate the gene into the cell's DNA and are unlikely to trigger an immune response compared to other viral vectors. However, these viruses can only fit small amounts of DNA. Scientists have also experimented with the use of non-viral vectors and hybrid vectors. Liposomes are phospholipid spheres which are used to transport medicines to cells. Scientists have placed functional genes in liposomes to treat genetic mutations. However, liposomes are ineffective, due to the fact that they can be toxic and do not target specific cells. All vectors used in gene therapy have disadvantages. This is why scientists are currently combining viral and non-viral vector methods. Virosomes are liposomes covered with viral proteins. They can be used to target specific cells, but are less likely to cause an immune response. In future, researchers will gravitate towards the use of hybrid and non-viral vectors in gene therapy; as they are safe and efficient in targeting cells compared to viral vectors.
A major disadvantage of gene therapy is that there is the potential for a dangerous immune response. Naturally, the immune system fights foreign pathogens. This function is crucial for health, However, it can cause dangerous side effects during gene therapy. As mentioned previously, gene therapy patient Jesse Gelsinger died from multiple organ failure, after treatment for an X-linked liver disease. Since Gelsinger's death in 1999, gene therapy researchers have focused on using the lowest effective dose of the corrected DNA possible. Immunosuppressants have also been used to eliminate the risk of immune response. However, immunosuppressants can have serious side effects such as severe infection and uncontrollable bleeding. In cystic fibrosis patients, the use of immunosuppressants would likely result in death due to lung infection. One way to limit immune response without increasing infection risk is by Inserting the corrected gene into the target cells outside of the body. Normally, vectors are injected, swallowed or inhaled by patients depending on the location of the target cells. This method of gene therapy is called in-vivo because the treatment occurs inside the body. The ex vivo method of gene therapy involves harvesting target cells and growing them in a petri dish via tissue culture. By using the ex vivo method, a dangerous immune system response cannot occur and scientists can check that the gene has been successfully implanted into the genome. In cystic fibrosis, the epithelial lung cells are harvested via transthoracic lung biopsy; a procedure in which a small incision is made and a needle is injected into the lung. Gene therapy is dangerous, due to the likelihood of a negative immune response. However, scientists are continually learning how to improve this technology and how to balance its effectiveness with safety. In future, ex vivo gene therapy will become more common as it eliminates the chance of an immune system response.
Another disadvantage of gene therapy is the fact that corrected gene copies can integrate into the genome incorrectly. For a gene therapy treatment to work, the corrected gene must implant itself into the genome. Certain viruses such as adenoviruses do not integrate into the genome permanently and therefore the corrected copy of the diseased gene is removed within a few weeks. Retroviruses, on the other hand, integrate into the cell's genome permanently. However, retroviruses have been found to integrate into random parts of the genome. 1999 and 2006, researchers performed gene therapy on 5 children with a genetic immunodeficiency, using retroviruses as vectors. By 2006, all 5 of these children had developed leukaemia as a result of the vector implanting into an incorrect part of the genome. When the corrected gene integrated into the genome, a frame shift occured due to insertional mutagenesis. This meant that existing gene was disrupted, creating an oncogene (cancer-causing gene) known as LMO2. Adeno associated viruses and non-viral vectors do not integrate into random parts of the genome. Therefore, it is likely that scientists will abandon the use of retroviruses and adenoviruses for gene therapy in favour of adeno associated viruses and non-viral vectors.
It is important to note that gene therapy can only be considered when certain biological prerequisites have been met. Firstly, gene therapy only works when used as a treatment for monogenic (single gene) mutations. Many genetic conditions such as heart disease, autism, schizophrenia, diabetes and high blood pressure involve multiple point mutations on different genes. Secondly, gene therapy will not work if the disease has multiple causes. In some genetic conditions, such as autism; symptoms are caused by a complex web of point mutations. It is difficult to figure out which gene to target if the disease can be caused by an unknown variety of mutations. Thirdly, gene therapy will not be effective if environmental factors are present. Sometimes a genetic mutation is asymptomatic until certain environmental conditions are met. Finally, many genetic disorders are caused by larger scale chromosome mutations (duplications, inversions, aneuploidies etc). At present, scientists cannot treat these disorders. At present, gene therapy can only treat a small number of simple genetic mutations. In the near future, it is likely that scientists will improve current treatments and develop new gene therapy methods such as germline therapy as well as therapies that target large-scale chromosome mutations. Germline gene therapy involves using vectors to correct genetic abnormalities in gametes. Scientists have theorised that it would be effective and that the patient would be disease free for life. Researchers are currently experimenting with the use of genes for chromosome silencing. The XIST gene is found on the X chromosome. Researchers have found that the XIST gene can be harvested and inserted into other chromosomes with a vector, silencing the chromosome's activity. In future, this method could be used to turn off extra chromosomes in cells. However, this therapy would need to target multiple cells and at present, this cannot be done.
Gene therapy is a rapidly developing technology which aims to replace faulty genes with properly functioning copies to cure disease.
At present, there are major disadvantages to gene therapy. Firstly, it is difficult to target specific cells. However, researchers are continually developing more efficient vectors such as virosomes. Secondly, gene therapy can cause dangerous immune responses, as seen in the case of Jesse Gelsinger. However, researchers have begun to use vectors that don't cause an immune response; such as adeno associated viruses, virosomes and liposomes. Scientists have also harvested cells and performed gene therapy outside the body (ex vivo). This method of gene therapy does not cause an immune response and scientists can check whether or not the functional gene has been implanted into the genome. In future, it is likely that ex vivo gene therapy will become more common, as it is safer than in Vivo gene therapy. Thirdly, for gene therapy to succeed, the functional gene must integrate into the genome, in the right location (on the end of a chromosome). vectors such as the adenovirus do not integrate into the genome permanently; and retroviruses implant into random parts of the genome, causing frameshift mutations (as seen in the gene therapy-leukemia incident). Scientists are continually investigating the use of safer vectors, such as adeno associated viruses, liposomes and virosomes. Finally, it is important to note that gene therapy currently has limited uses. Disorders that involve multiple genes, chromosome mutations and/or environmental factors cannot be treated with gene therapy. In light of the aforementioned evidence, it is apparent that gene therapy is currently dangerous and ineffective. However, gene therapy is an experimental technology which has only been trialled in humans since 1990. Therefore, it is too early to rule out the use of gene therapy for genetic conditions such as
CF.