The Evolution And Development Of Gene Therapy

Abstract

The following paper presented follows gene therapy throughout its journey. Analyzing data from the past to the present and the possibilities that are to come in the future, we gain a better understanding of what gene therapy is and why it is important in our society today. “Gene therapy is an experimental technique that uses genes to treat or prevent disease,” (What Is Gene Therapy?). This is done by replacing a mutated that causes disease with a healthy copy of the gene, inactivating a mutated gene that is functioning improperly and introducing a new gene into the body to help fight a disease (What Is Gene Therapy?). Even though gene therapy seems to be a promising new way to treat several diseases, this remains a risky technique that is still under study to make sure it will be safe and effective before the approval from FDA and CPMP is released to the general public.

Introduction

Gene therapy is a profound new science that has only just begun to emerge in the scientific community as a way of providing opportunities to help civilization and society as a whole in fighting genetic diseases and becoming healthier. The goal of gene therapy is to replace or enhance the biological function of damaged genes. Through the use of the human genome to work from the origin, gene therapy can restructure what needs to be repaired. Improving a patient’s DNA to cure disease or undesirable hereditary traits can assist in creating a healthier and more productive society. Gene therapy looks promising and has immense potential to help thousands in the future generations to come. Although it does seem that it may take some time to realize its full potential, gene therapy looks like it will probably have a large impact on the treatment of human disease in the coming years (Anderson). To have a better understanding of where this new technology is headed towards, we must analyze both the past and its present to accurately estimate gene therapy’s future.

Literature Review

After evaluating the past of gene therapy and researching the progression the scientific community has made in the understanding of the matter, it can be concluded that gene therapy is not at its breaking point to emerge as a cure for genetic diseases and disorders. Researching through the past sixty years, we can estimate the rate at which gene therapy is evolving. In 1962, scientists began working on the genetics of a human cell (Szybalski). Using the HPRT system, scientists were able to extract and isolate several patient’s bone marrow cell cultures, which had lost HPRT gene activity (Szybalski). The HPRT1 gene provides instructions for the production of enzymes that regulate and recycle purines, also known as hypoxanthine phosphoribosyltransferase enzyme (HPRT1 Gene). After experimentation on these cells, the scientists made a system that permitted the selection of mutants. Two years after developing these cells and conducting experiments on them, the researchers learned of a neurological syndrome caused by the loss of the enzyme. Then discovered that their developed cells had the same syndrome which led to curing it, but it could only be done in vitro. Therefore, this experiment became the first form of human gene therapy (Szybalski).

In 1989, RAC approved the first human gene therapy trial, treating ten patients who had ADA deficiency, which is a form of immunodeficiency. The initial research was approved for a study up to two patients but later led to a limit of only two. The patients both regained normal peripheral T lymphocyte counts during this study, and they retained for up to two years after their last treatments (Knoell). The results from this clinical trial should be interpreted with caution. Though we have progressed throughout the years, we still need to observe some of the long term effects of gene therapy and on the patients before we use this process on a larger clinical setting. If negative effects were to present themselves in patients in the long term, it would be crucial for scientists and the FDA to know of them before releasing any approval to the general public. Without this type of data, it could result in a mass outbreak of possible illness, disease or death caused by gene therapy that we do not know how to tackle.

In 1997, the first Gene Therapy Policy Conference was held, where they discussed the ethical issues that came with gene therapy (Anderson). It was concluded that the enhancement of gene therapy could slip through the regulatory process if RAC and FDA were not attentive (Ginn). In 2000, the gene therapy research community celebrated the first report of successful treatment of genetic disease by gene therapy. French researcher, Alan Fisher, was able to cure children with similar kinds of immune system disorder. Unfortunately, they were left feeling obsolete when one of the initial patients in the French trail developed a T cell leukemia thirty months after treatment. This was caused due to a direct result of the gene transfer vector used (Ginn). The trial was then placed on a voluntary hold while the cause was under investigation. This led to the improvement of vector safety to reduce the likelihood of similar events occurring in future clinical trials. Vectors are used to bring new DNA to the location where it will be replacing the faulty genome section. If these vectors reactive inadequately or travel to an unintended location the results could be dire. Almost a decade later, an international trial applying a vector with improved safety features were opened and began treating patients (Ginn). For advancement to occur, there will be continuous mistakes. The priority is to minimize the effect these mistakes may have on the patients and to have a large number of trials to weed out any of the side-effects of gene therapy.

Currently, gene therapy is being tested on humans today. In our present day, over 300 clinical protocols have been approved (Anderson). Most of the clinical trials in gene therapy have been targeted for the treatment of cancer, cardiovascular disease and inherited monogenic diseases (Ginn). The expediency of human gene therapy throughout these trails have been experimented with more than 1800 patients with concurrent studied throughout the world (Ginn). Even though there has been initial success, there has been an increasing amount of skepticism about the clinical usefulness of such advanced, expensive treatment strategies (Knoell). As seen in the past, there is a need for improved gene-delivery vectors that can target sites within the body, transfer greater efficiency, and reduce risk to patients (Knoell). Ongoing efforts focus on improving vector design and to limit the toxicity and enhance the efficiency of gene transfer (Knoell). Improving vectors are currently the most challenging problem in gene therapy and need to reach a certain level of safety before being released to the general public.

In the present day, there are two types of gene therapy: viral and nonviral methods. Viral methods carry the new gene or DNA strand in a virus i.e. the pox virus, retrovirus, or even herpes simplex virus. Non-viral methods are used on a large scale production of the gene by typically using the patient's cells to create a smaller chance that the immune system will react to the treatment. A current form of technology linked with the non-viral gene therapy method is the use of electroporation. Electroporation uses an external electric field to apply the desired gene through the cell’s membrane into the cell (Anderson).

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The most serious problem for cells is the destruction of the implant by the host’s immune system. To overcome this challenge, strategies are being developed and some successes have been reported. The choice of strategy needs to be dependent on the nature of the immune response for it to appropriately match the immunoprotective strategies. Some problems that occur are in xenografts and allogeneic cells’ T-cell mediated immune response. Some strategies to overcome this issue include using pure populations of cells that are not contaminated with leukocytes or endothelial cells and minimize injury to the site of implantation. Also, some target sites may have decreased immune responsiveness. For example, the brain, eye and spinal cord have lessened and delayed immune response to foreign cells (Anderson).

Modifying the immune system is done by immunosuppressive drugs, but islet cells are still sensitive to many of the standard immunosuppressive drugs, therefore leading to scientists to aggressively research immunoisolation strategies (Anderson). The immune system remains the primary problem today. Although some of the responses to the problems seem to have promising data, there are still many obstacles to overcome than ever before. It seems as if the more we research and understand gene therapy, more problems continue to emerge. The current issue with the patient’s or host’s immune system continues to be a major issue that stalls the progress of gene therapy.

There are still several factors that are involved with maintaining the stable expression of gene genes after transfer (Anderson). First, the regulatory sequence that controls gene expression often do not remain active. There is a habit for the cell to recognize foreign promoters/ The immune system is designed to recognize and eliminate foreign gene products and cells that produce foreign protein. Growth factors in maintaining gene expression are not understood well. A new synthesized normal protein will appear abnormal to an immune system that has never been exposed to it. Second, even if the gene stays active within the cell, the cell sometimes dies. The factors that lead to the low efficiency of gene transfer and expression in human patients include the fact that we still lack the basics of understanding how vectors should be constructed, what regulatory sequences are appropriate for each cell type, and how in vivo immune defenses can be overcome (Anderson). These issues must be handled before there are any advancements in gene therapy. Some of the recommendations for safe handling and processing of cells are outlined by the FDA and the European Union Committee for Proprietary Medicinal Products (CPMP) (Anderson). These recommendations include standard screens for sterility, mycoplasma, and a variety of human viruses (Anderson).

Before the present day, gene therapy was not seen as an ethical act, but new data shows that according to public opinion, using gene therapy for the treatment of serious disease is now accepted as ethically appropriate. The new ethical issue that has been presented in this generation is the use of gene therapy for non-disease conditions, for example, functional enhancement of cosmetic purposes (Anderson). With the currently ongoing research and the problems that have been presented, until there are more results about the long-term effects in the treatment of disease, it should not be used for any other purpose than the current medical intentions. There is a fear within society that there may be an emergence of abuse of the new technologies. Within our opinion, before this technology being released to the public, the government along with the FDA need to create a set of laws and rules about the ethical issues at question that can be accepted by the majority of the public. The current guidelines and ethical issues with the advances in gene therapy include that only suitable diseases, in humans and their pets, should be treated (Szybalski).

Taking into account the hurdles, ethical, and scientific guidelines that gene therapy has to overcome, we don’t believe that gene therapy is going to make its’ breakthrough any time soon. The obstacles presented in this paper will take a significant amount of time to surpass and gene therapy will not be released to the public until they are.

The future of gene therapy is expected to see a combination of both genetic and nanoparticle engineering (Zhang). Despite all of the excitement around the breakthroughs in gene therapy, this field is still in its early stages. Even though in vitro studies and tests on animals have presented the use of nanoparticles as gene delivery methods, only a small amount of clinical trials of gene therapy have been completed, currently being researched, or underway (Zhang). Before any convincing results can be set there needs to be many more trials and tests. Results must include both long-term and short-term effects. More importantly, scientists in this field should concentrate on the development of more efficient delivery vectors for non-viral or virals origins (Szybalski). Furthermore, there must be development of suitable regulatory circuits and systems for repairing faulty genes, to ensure patient survival versus improving current gene systems to create a better quality of life (Szybalski). Future trials require better design trials to prove clinical utility (Knoell). For example, long term and stable levels of gene expression in vivo in a range of cell types is still to be accomplished. Once it is, the next step would be the achieve gene expression that can be regulated. The final goal would be to figure out a strategy to use regulatory sequences that respond to the patient’s physiological signals or to use drugs that can be used to control the level of gene activity (Anderson).

To elaborate on the production of drugs, another future goal is to manufacture pharmaceutical drugs to carry out gene therapy itself. One of the controversies that lay in this topic of retroviral vectors, is the possibility that a replication-competent retrovirus (RCR) could be created during the manufacturing process (Anderson). Since retroviral vectors are created in packaging cells that contain packaging defective viral genome they have a high tendency for recombination and this possibility always remains present. Another concern arises because all mammalian cells contain endogenous retroviruses. If additional viral sequences are incorporated in the RCR, it could potentially produce a pathogenic virus (Anderson). Considering the role that the pharmaceutical industry has in the medical community, we believe that one day there will be safe pharmaceutical drugs that can carry out the effects of gene therapy rather than having to go through actual treatment. This is an essential part in the development of gene therapy and introducing gene therapy to the general public as a real treatment rather than merely a concept.

Conclusion

Throughout our research in gene therapy’s past, where we currently stand with development and all of the obstacles that researchers in the field must still overcome, we can assume that gene therapy may finally emerge towards the end of our lifetime. Gene therapy researchers still have a long way to go to prove that it is a safe and effective method of curing genetic diseases. There still needs to be extensive research on the procedures of in vivo methods and more tests done on humans to perform trials that will depict accurately all the effects of gene therapy. Finally, an ethical standard and a set of guidelines concerning gene therapy still need to be released where the majority of the general public is willing to follow. Until the FDA and the CPMP agree that gene therapy is safe to be used as a medicinal practice, not just as trials and experiments, gene therapy remains only as a possibility of the future and not a cure. Once again, even though gene therapy has a long way to go, in our opinion, it will one day become an essential practice to cure and treat genetic diseases and disorders.