Gene Therapy: Future Perspectives And Ethics
Advantages of Gene therapy: Future Perspectives and Ethics
Gene Therapy History
In the 80s, advances in molecular biology have allowed the human genes were cloned and sequenced. Scientists looked for a method to facilitate the production of proteins - such as insulin - viewed introducing human genes into the DNA of bacteria. Bacteria, genetically modified, then began to produce the corresponding protein, which could be collected and injected into people who could not produce naturally. After, on September 14 of 1990, researchers at the National Institutes of Health in the United States, conducted the first gene therapy approved in Ashanti DeSilva, 4 years old, who was born with a rare genetic disease called Severe Combined Immunodeficiency (SCID), she did not have a healthy …show more content…
immune system being vulnerable to contact with any disease-causing microorganism. Unfortunately, patients with this disorder often develop many infections and rarely survive until adulthood. In this case, doctors collected white blood cells of the body of the child, and cultured the cells in the laboratory. In the second phase, inserted the missing gene into cells and reintroduced modified the bloodstream of the patient 's white blood cells genetically. As a result, laboratory’s tests showed that the therapy strengthened the immune system Ashanti, she stopped getting recurrent colds and could return to school. This procedure not healed; genetically modified leukocytes only worked for a few months, and the process had to be repeated often. (Wirth, & Yla-Herttuala, 2013; Herzog, 2009; Kelly, 2007).
Although this simplified explanation of gene therapy may sound like a happy ending, is just an initial optimistic chapter in a long history, and the journey to the first authorized gene therapy was troubled and full of controversy. In addition, the biology of gene therapy in humans is very complex, and there are many techniques that need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. Otherwise, scientists have taken the initiative to introduce genes directly into human cells, focusing on diseases caused by defects in single genes, such as cystic fibrosis, hemophilia and muscular dystrophy. However, this goal was much more difficult to achieve than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and its right position in the genome. (Wirth, Parker, & Yla-Herttuala, 2013; Herzog, 2009; Kelly, 2007).
Background
The gene therapy has been attached significantly in the modern society’s concerns approached by new generations’ advances. Because of this, the worldwide population has had some inevitable questions answered by specialists that provide essential informations about how important this process is, how it superficially works and what is its impact over the biotechnological development. (Herzog, 2009; Kelly, 2007).
Let’s start in the initial principle. What is basically a gene? The majority of the body cells has a nucleus, localized in the center of the cell, which commands the cellular reactions and houses pairs of chromosomes (composed by genetic code that is known as deoxyribonucleic acid - DNA molecule). These spiral staircases stock information in discrete chunks or blocks called genes, heredity functional unit that provide the genetic diversity between individuals. The DNA sequences are able to replicate their own content by themselves through a process denominated replication, and they also produce proteins indirectly by a method called transduction (that keep the cell operation working). But what is gene therapy actually? Unusually, during these cellular processes, normal cells commit mistakes that result in mutations whose accumulation can causes genetic diseases, and it is in this point where the gene therapy is used (Herzog, 2009; Kelly, 2007). Wirth, Parker and Yla-Herttuala’s studies (2013) showed the following: The European Medicines Agency (EMA) defines that “a gene therapy medicinal product is a biological medicinal product which fulfils the following two characteristics: (a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; (b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. Gene therapy medicinal products shall not include vaccines against infectious diseases”. The US Food and Drug Administration (FDA) defines gene therapy as products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient.” (Wirth, Parker, & Yla-Herttuala, 2013)
These conditions show what the goal of gene transfer is. The procedures of gene therapy in vivo consist of transferring the DNA directly to the cells or tissues of the patient. In ex vivo procedures, the DNA is first transferred to isolated cells of an organism, previously grown in the laboratory. The isolated cells are modified and thus can be introduced into the patient. This method is indirect and more time consuming, but offers the advantage of a better transfer efficiency and the ability to select and expand the modified cells prior to reintroduction. However, for initiating this cascade of events, the new gene needs to be transported toward its action site without being target of the cellular lysis. Therefore, capsule-shaped recipient are available to carry the information with safety until its destination (they are named vectors, and virus are commonly used as an ideal vector). Also, it is important to point out that systemic administration of gene therapy vectors is fairly problematic. Direct vector injection into the bloodstream does not work the way that researchers would like. Often, the body 's natural defense is able to remove the virus from the blood before they can have the opportunity to find and kill the tumor. The liver is particularly well suited to purify our blood and does a good job in removing viral particles (especially in the case of adenovirus, the most common viral vector in gene therapy of cancer). (Herzog, 2009; Kelly, 2007).
Future Perspectives
Nowadays, there are many genetic disorders that are haunting the human mind. This way, gene therapy shows up as a workable tool to treat that problem. For example, taking the blindness from blinds away. Retinits pigmentosa, eye disease caused by combination of multiple mutations in the encoder gene to rhodopsin, prevents a proper visual transduction causing blindness effects gradually which can provide a total loss of vision due to breakdown of photoreceptor cells (that transform light energy into nerve signals. In this case, gene therapy is an alternative treatment to give back the impaired function for rhodopsin gene. Nearly experiments prove that it is possible by two simple methods: replacing the affected gene for its identic copy, or turning off the mutation able to cause deadly effect for photoreceptor cells. Other abnormalities on ophthalmoscopy showed able to receive the gene therapy treatment too such as Leber’s Congenital Amaurosis (LCA), Stargardt disease and age related macular degeneration. (Al-Saikhan, 2013; MacLaren, Groppe, Barnard, Cottriall, Tolmachova, Seymour, Clark, During, Cremers, Black, Lotery, Downes, Webster, & Seabra, 2014).
Another gene strategy is struggling against the cancer damages and combating its dissemination resulting in metastases. The main aim this therapy involves to eliminate significantly or totally the cancer cells without unwanted side effects (death of normal cell). This process can be reached directly through a vector that supplies a gene able to spur cell death. Otherwise, indirectly, inducing an immune response can destroy even occult tumor cells. Generally, the cancer treatments are using in partnership with other traditional methods such as gene therapy plus chemotherapy. However, the efficient amount of vector to infect all the cancer cells would cause severe unwanted side effects, so scientists need to worry that relatively only few tumor cells are going to be infected. (Curiel, D. T., & Douglas, J. T., 2005).
Interested Studies’ at Cornell University have obtained positive outcomes in the attempt to neutralize the impacts of nicotine in the human body aiming of quit smoking. The present experiment, utilizing mice with samples, introduces a specific antibody able to bond to nicotine chemical preventing it from reaching the brain, in the other words, the anti-nicotine defense cell blocks the entry of the undesirable toxin in the tissues inhibiting possible neural effects. Consequently, no have changes in the normal conditions of the organism commonly caused by nicotine doses such as increase of heart rate and blood pressure. (Hicks, Rosenberg, De, Pagovich, Young, Qiu, Kaminsky, Hackett, Worgall, Janda, Davisson, & Crystal, 2012).
Lately, the gene therapy has been useful for treating wide range of hereditary diseases. This successful idea has reached all the fields of biotechnology such as design babies, deletion of gene mutation, animal hybrids, animal and human cloning, protocols of pre-natal diseases, basic skills improvement, treatments for Alzheimer and depression, monogenic disorders, Parkinson’s disease and more. Science has no Ego and its ideas change all the time, so future prospects never will be highlighted negatively by the researches because the researches do not have ending. (Coutelle, & Waddington, 2012; Kimmelman, 2010).
Safety and ethics aspects Figure retrieved from: http://geneticamolecularehumana.blogspot.ca/2011/12/o-lado-etico-da-terapia-genica.html
Ethics in researches will always be a mystery. Although many fiscal organizations analyze the conditions and perspectives of the experiments, few illegal laboratories works normally questioning the rights of doing researches. However, several scientists lead conscientious projects and professional works aiming the welfare of human beings. In a gene therapy ethics all care is noticeable. There are sophisticated and effective trainings, capacitation courses and programs, hard selection process for new stuff, well-equipped labs, easily available maps and clinical protocols. Every researcher take care about the life.
All the experiments are supervised and checked for rigid ethics councils. In terms of the quality and stability to express transgene, there are technical issues which has induced concerns to justify the experiment. Some factories should be respected such as:
What are the chemical information of the DNA and vector to be used?
Does the practiced technique have risks for the patient?
The fear of human genetic engineering difficulties the conduction of human gene therapy in some cases.
Is the load vector trustful and acceptable according to the ethics norms?
Do patients or volunteers know surely about the concerns of the experiment? (Wirth, Parker, & Yla-Herttuala, 2013)
Finally, Wirth, Parker, & Yla-Herttuala (2013) claims that “the main risks arise from the characteristics of these vectors to integrate into gene regulatory areas or into transcriptionally active areas, respectively, which potentially can adversely result in insertional mutagenesis and oncogenesis. In order to circumvent these problems, targeted integration of transgenes to predetermined genomic sites has been one of the most important topics in current vector development”. Thus, the modern society seeks challenges that encourage the science to search new knowledge and solve the old problems that will always appear on the way. And, it will repeat again and again a vicious cycle for biotechnological development and intellectual upgrading. (Wirth, Parker, & Yla-Herttuala, 2013; Herzog, & Zolotukhin, 2010).
References
Al-Saikhan, F. I. (2013). The gene therapy revolution in ophthalmology. Saudi Journal of Ophthalmoly, 27, 107-111.
Coutelle, C., & Waddington, S. N. (2012). Prenatal gene therapy: Concepts, methods, and protocols. (1st ed., Vol. 891, pp. 1-393). Totowa, NJ: Human Press. Retrieved from http://books1.scholarsportal.info.ezproxy.library.yorku.ca/viewdoc.html?id=/ebooks/ebooks2/springer/2012-07-23/1/9781617798733
Curiel, D. T., & Douglas, J. T. (2005). Cancer gene therapy. (pp. 1-489). Totowa, NJ: Humana Press Inc.
Herzog, R. W. (2009). Gene therapy immunology. (pp. 1-397). Hoboken, NJ: Jonh Wiley & Sons, Inc.
Herzog, R. W., & Zolotukhin, S. (2010). A guide to human gene therapy. (pp. 1-388). Singapore: World scientific Publishing Co. Pte. Ltd.
Hicks, M.J., Rosenberg, J.B., De, B.P., Pagovich, O.E., Young, C.N., Qiu, J., Kaminsky, S.M., Hackett, N.R., Worgall, S., Janda, K.D., Davisson, R.L., & Crystal, R.G.
(2012). AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation. Science Translational Medicine, 4 (140), pp. 140ra87
Kelly, E. B. (2007). Gene therapy. (1st ed., Vol. 1, pp. 4-192). Westport, Conn: Greenwood Press.
Kimmelman, J. (2010). Gene transfer and the ethics of first-in-human research: Lost in translation. (1st ed., Vol. 1, pp. 1-205). Cambridge, NY: Cambridge University Press. Retrieved from https://www.library.yorku.ca/find/Record/2465972
MacLaren, R.E., Groppe, M., Barnard, A.R., Cottriall, C.L., Tolmachova, T., Seymour, L., Clark, K.R., During, M.J., Cremers, E.P.M., Black, G.C.M., Lotery, A.J., Downes, S.M., Webster, A.R., & Seabra, M.C. (2014). Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. The Lancet, pp. 1-9. Published online January 16, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62117-0
Torjesen, I. (2014). Gene therapy inherited blindness shows promise in first clinical trial. BMJ,
1-1. Wirth, T., Parker, N., & Yla-Herttuala S. (2013). History of gene therapy. Elsevier B.V, pp.162-168.
Gene Therapy History
In the 80s, advances in molecular biology have allowed the human genes were cloned and sequenced. Scientists looked for a method to facilitate the production of proteins - such as insulin - viewed introducing human genes into the DNA of bacteria. Bacteria, genetically modified, then began to produce the corresponding protein, which could be collected and injected into people who could not produce naturally. After, on September 14 of 1990, researchers at the National Institutes of Health in the United States, conducted the first gene therapy approved in Ashanti DeSilva, 4 years old, who was born with a rare genetic disease called Severe Combined Immunodeficiency (SCID), she did not have a healthy …show more content…
immune system being vulnerable to contact with any disease-causing microorganism. Unfortunately, patients with this disorder often develop many infections and rarely survive until adulthood. In this case, doctors collected white blood cells of the body of the child, and cultured the cells in the laboratory. In the second phase, inserted the missing gene into cells and reintroduced modified the bloodstream of the patient 's white blood cells genetically. As a result, laboratory’s tests showed that the therapy strengthened the immune system Ashanti, she stopped getting recurrent colds and could return to school. This procedure not healed; genetically modified leukocytes only worked for a few months, and the process had to be repeated often. (Wirth, & Yla-Herttuala, 2013; Herzog, 2009; Kelly, 2007).
Although this simplified explanation of gene therapy may sound like a happy ending, is just an initial optimistic chapter in a long history, and the journey to the first authorized gene therapy was troubled and full of controversy. In addition, the biology of gene therapy in humans is very complex, and there are many techniques that need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. Otherwise, scientists have taken the initiative to introduce genes directly into human cells, focusing on diseases caused by defects in single genes, such as cystic fibrosis, hemophilia and muscular dystrophy. However, this goal was much more difficult to achieve than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and its right position in the genome. (Wirth, Parker, & Yla-Herttuala, 2013; Herzog, 2009; Kelly, 2007).
Background
The gene therapy has been attached significantly in the modern society’s concerns approached by new generations’ advances. Because of this, the worldwide population has had some inevitable questions answered by specialists that provide essential informations about how important this process is, how it superficially works and what is its impact over the biotechnological development. (Herzog, 2009; Kelly, 2007).
Let’s start in the initial principle. What is basically a gene? The majority of the body cells has a nucleus, localized in the center of the cell, which commands the cellular reactions and houses pairs of chromosomes (composed by genetic code that is known as deoxyribonucleic acid - DNA molecule). These spiral staircases stock information in discrete chunks or blocks called genes, heredity functional unit that provide the genetic diversity between individuals. The DNA sequences are able to replicate their own content by themselves through a process denominated replication, and they also produce proteins indirectly by a method called transduction (that keep the cell operation working). But what is gene therapy actually? Unusually, during these cellular processes, normal cells commit mistakes that result in mutations whose accumulation can causes genetic diseases, and it is in this point where the gene therapy is used (Herzog, 2009; Kelly, 2007). Wirth, Parker and Yla-Herttuala’s studies (2013) showed the following: The European Medicines Agency (EMA) defines that “a gene therapy medicinal product is a biological medicinal product which fulfils the following two characteristics: (a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; (b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. Gene therapy medicinal products shall not include vaccines against infectious diseases”. The US Food and Drug Administration (FDA) defines gene therapy as products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient.” (Wirth, Parker, & Yla-Herttuala, 2013)
These conditions show what the goal of gene transfer is. The procedures of gene therapy in vivo consist of transferring the DNA directly to the cells or tissues of the patient. In ex vivo procedures, the DNA is first transferred to isolated cells of an organism, previously grown in the laboratory. The isolated cells are modified and thus can be introduced into the patient. This method is indirect and more time consuming, but offers the advantage of a better transfer efficiency and the ability to select and expand the modified cells prior to reintroduction. However, for initiating this cascade of events, the new gene needs to be transported toward its action site without being target of the cellular lysis. Therefore, capsule-shaped recipient are available to carry the information with safety until its destination (they are named vectors, and virus are commonly used as an ideal vector). Also, it is important to point out that systemic administration of gene therapy vectors is fairly problematic. Direct vector injection into the bloodstream does not work the way that researchers would like. Often, the body 's natural defense is able to remove the virus from the blood before they can have the opportunity to find and kill the tumor. The liver is particularly well suited to purify our blood and does a good job in removing viral particles (especially in the case of adenovirus, the most common viral vector in gene therapy of cancer). (Herzog, 2009; Kelly, 2007).
Future Perspectives
Nowadays, there are many genetic disorders that are haunting the human mind. This way, gene therapy shows up as a workable tool to treat that problem. For example, taking the blindness from blinds away. Retinits pigmentosa, eye disease caused by combination of multiple mutations in the encoder gene to rhodopsin, prevents a proper visual transduction causing blindness effects gradually which can provide a total loss of vision due to breakdown of photoreceptor cells (that transform light energy into nerve signals. In this case, gene therapy is an alternative treatment to give back the impaired function for rhodopsin gene. Nearly experiments prove that it is possible by two simple methods: replacing the affected gene for its identic copy, or turning off the mutation able to cause deadly effect for photoreceptor cells. Other abnormalities on ophthalmoscopy showed able to receive the gene therapy treatment too such as Leber’s Congenital Amaurosis (LCA), Stargardt disease and age related macular degeneration. (Al-Saikhan, 2013; MacLaren, Groppe, Barnard, Cottriall, Tolmachova, Seymour, Clark, During, Cremers, Black, Lotery, Downes, Webster, & Seabra, 2014).
Another gene strategy is struggling against the cancer damages and combating its dissemination resulting in metastases. The main aim this therapy involves to eliminate significantly or totally the cancer cells without unwanted side effects (death of normal cell). This process can be reached directly through a vector that supplies a gene able to spur cell death. Otherwise, indirectly, inducing an immune response can destroy even occult tumor cells. Generally, the cancer treatments are using in partnership with other traditional methods such as gene therapy plus chemotherapy. However, the efficient amount of vector to infect all the cancer cells would cause severe unwanted side effects, so scientists need to worry that relatively only few tumor cells are going to be infected. (Curiel, D. T., & Douglas, J. T., 2005).
Interested Studies’ at Cornell University have obtained positive outcomes in the attempt to neutralize the impacts of nicotine in the human body aiming of quit smoking. The present experiment, utilizing mice with samples, introduces a specific antibody able to bond to nicotine chemical preventing it from reaching the brain, in the other words, the anti-nicotine defense cell blocks the entry of the undesirable toxin in the tissues inhibiting possible neural effects. Consequently, no have changes in the normal conditions of the organism commonly caused by nicotine doses such as increase of heart rate and blood pressure. (Hicks, Rosenberg, De, Pagovich, Young, Qiu, Kaminsky, Hackett, Worgall, Janda, Davisson, & Crystal, 2012).
Lately, the gene therapy has been useful for treating wide range of hereditary diseases. This successful idea has reached all the fields of biotechnology such as design babies, deletion of gene mutation, animal hybrids, animal and human cloning, protocols of pre-natal diseases, basic skills improvement, treatments for Alzheimer and depression, monogenic disorders, Parkinson’s disease and more. Science has no Ego and its ideas change all the time, so future prospects never will be highlighted negatively by the researches because the researches do not have ending. (Coutelle, & Waddington, 2012; Kimmelman, 2010).
Safety and ethics aspects Figure retrieved from: http://geneticamolecularehumana.blogspot.ca/2011/12/o-lado-etico-da-terapia-genica.html
Ethics in researches will always be a mystery. Although many fiscal organizations analyze the conditions and perspectives of the experiments, few illegal laboratories works normally questioning the rights of doing researches. However, several scientists lead conscientious projects and professional works aiming the welfare of human beings. In a gene therapy ethics all care is noticeable. There are sophisticated and effective trainings, capacitation courses and programs, hard selection process for new stuff, well-equipped labs, easily available maps and clinical protocols. Every researcher take care about the life.
All the experiments are supervised and checked for rigid ethics councils. In terms of the quality and stability to express transgene, there are technical issues which has induced concerns to justify the experiment. Some factories should be respected such as:
What are the chemical information of the DNA and vector to be used?
Does the practiced technique have risks for the patient?
The fear of human genetic engineering difficulties the conduction of human gene therapy in some cases.
Is the load vector trustful and acceptable according to the ethics norms?
Do patients or volunteers know surely about the concerns of the experiment? (Wirth, Parker, & Yla-Herttuala, 2013)
Finally, Wirth, Parker, & Yla-Herttuala (2013) claims that “the main risks arise from the characteristics of these vectors to integrate into gene regulatory areas or into transcriptionally active areas, respectively, which potentially can adversely result in insertional mutagenesis and oncogenesis. In order to circumvent these problems, targeted integration of transgenes to predetermined genomic sites has been one of the most important topics in current vector development”. Thus, the modern society seeks challenges that encourage the science to search new knowledge and solve the old problems that will always appear on the way. And, it will repeat again and again a vicious cycle for biotechnological development and intellectual upgrading. (Wirth, Parker, & Yla-Herttuala, 2013; Herzog, & Zolotukhin, 2010).
References
Al-Saikhan, F. I. (2013). The gene therapy revolution in ophthalmology. Saudi Journal of Ophthalmoly, 27, 107-111.
Coutelle, C., & Waddington, S. N. (2012). Prenatal gene therapy: Concepts, methods, and protocols. (1st ed., Vol. 891, pp. 1-393). Totowa, NJ: Human Press. Retrieved from http://books1.scholarsportal.info.ezproxy.library.yorku.ca/viewdoc.html?id=/ebooks/ebooks2/springer/2012-07-23/1/9781617798733
Curiel, D. T., & Douglas, J. T. (2005). Cancer gene therapy. (pp. 1-489). Totowa, NJ: Humana Press Inc.
Herzog, R. W. (2009). Gene therapy immunology. (pp. 1-397). Hoboken, NJ: Jonh Wiley & Sons, Inc.
Herzog, R. W., & Zolotukhin, S. (2010). A guide to human gene therapy. (pp. 1-388). Singapore: World scientific Publishing Co. Pte. Ltd.
Hicks, M.J., Rosenberg, J.B., De, B.P., Pagovich, O.E., Young, C.N., Qiu, J., Kaminsky, S.M., Hackett, N.R., Worgall, S., Janda, K.D., Davisson, R.L., & Crystal, R.G.
(2012). AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation. Science Translational Medicine, 4 (140), pp. 140ra87
Kelly, E. B. (2007). Gene therapy. (1st ed., Vol. 1, pp. 4-192). Westport, Conn: Greenwood Press.
Kimmelman, J. (2010). Gene transfer and the ethics of first-in-human research: Lost in translation. (1st ed., Vol. 1, pp. 1-205). Cambridge, NY: Cambridge University Press. Retrieved from https://www.library.yorku.ca/find/Record/2465972
MacLaren, R.E., Groppe, M., Barnard, A.R., Cottriall, C.L., Tolmachova, T., Seymour, L., Clark, K.R., During, M.J., Cremers, E.P.M., Black, G.C.M., Lotery, A.J., Downes, S.M., Webster, A.R., & Seabra, M.C. (2014). Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. The Lancet, pp. 1-9. Published online January 16, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62117-0
Torjesen, I. (2014). Gene therapy inherited blindness shows promise in first clinical trial. BMJ,
1-1. Wirth, T., Parker, N., & Yla-Herttuala S. (2013). History of gene therapy. Elsevier B.V, pp.162-168.