Targeted Gene Therapy: A Fantasy or a Reality?

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Table of Contents

Introduction
Role of Targetted Gene Therapy in Various Immunodeficiency Disorders
Potential of Gene Therapy in the Treatment of Cancer
Genetic Therapy and Osteology
So Is Targetted Gene Therapy a Fact or a Fiction?
References

Introduction

Current advancements in the medical field have made reality the prospect of gene therapy, which was considered impossible not too long ago. While in the past, this was considered some sort of science fiction, the current leaps and bounds in technological advancements are making it possible to treat diseases from the very core structure, DNA. Initially, this therapy was confined only to the hematopoeitic stem cell population. However, now virtually any part of the human body can be treated with DNA therapy. The current scope of gene therapy is limitless, with a focus primarily on genetic and congenital disorders, cancer therapy and management of chronic pain and other degenerative conditions.

Many fields now come under the single heading of gene therapy. By definition, gene therapy is defined as a method whereby a normal gene can be introduced into the DNA sequence to replace any faulty genes leading to genetic disorders or diseases. This is, however, the primary and the initial type of genetic experiment and experience that was carried out when gene therapy initiated. The therapy can be carried out in two ways, either through germ cell gene therapy or somatic cell gene therapy.

The former is still in the experimental stages of development due to the many legal and ethical issues involved; however, by far, this method is the most effective one in treating and curing genetic conditions and diseases. (Rovephoenix, 2005, np) Now there are multiple models of genetic transfer and manipulation available, all showing some promise in the progression of the field.

The most common mode of introduction of a new gene into the DNA sequence is through the use of viruses. Many viruses are currently being used to carry out this function, and among them are included retroviruses, adenoviruses, adeno-associated viruses, and herpes simplex viruses.d this method has been used successfully in the past and continues to be used in many of the research works. However, the focus is also shifting towards non-viral methods of genetic transfer.

Non-viral methods may include the direct introduction of the gene into the target cells, liposomes, or binding the DNA to a specific target attaching molecule. (HGPI, 2007, np) the newer techniques are continuously developing, and with time only will the efficacy of each one understood.

The non-viral therapy, in many ways, increased the efficiency and results of the gene therapy that was facing hurdles due to the only mode of viral transfer. Viral modes of genetic transfer posed many problems such as virus recombination, oncogenic effects and unexpected immune response. The non-viral methods helped by increasing the simplicity of the introduction of the DNA into the body, the relatively less costly making of the drugs, and the absence of any immune response common to the viral model of gene delivery. (Niidome and Huang, 2002, pp 1648)

The non-viral techniques can be categorized into two forms, naked DNA delivery by any physical method and chemical mediated delivery. The physical mechanism is usually carried out on the tissues of skeletal muscle, liver, thyroid, heart muscle, urological organs, skin and tumours. Features such as electroporation, gene gun delivery method, ultrasound, hydrodynamic injection etc., are some of the techniques that are used to assist the physical introduction of DNA into the body. (Niidome and Huang, 2002, pp 1649)

The chemical methods of gene delivery include lipid-mediated gene delivery, peptide-mediated gene delivery, and polymer mediated gene delivery, respectively. Alongside, many new methods are being studied to improve the gene therapy procedures without the reliance on viral vectors. (Niidome and Huang, 2002, pp. 1650) These methods, however, are not completely perfect as yet and therefore, more research is required before any right methods can be categorized.

Currently, there are four therapeutic strategies that are used in genetics to treat diseases. Gene therapy proper is the method whereby a healthy gene is introduced into the target organ to replace the defective gene. Most of the development in this area refers to stem cell transplantation and is widely used in the brain. The second method works by reducing the expression of the mutated genes. For this purpose, some of the genes used include antisense oligonucleotides and ribozymes.

The third technique includes positional cloning strategies, where a mutation in the genes is used to create drugs for the treatment of the condition. Finally, the introduction of the embryonic tissue into the cell population is the fourth option, whereby the lost tissue is replenished. Except for the last one, all three techniques are being used successfully in clinical practise with promising results and better outcomes than conventional therapeutic methods. (Carter and Schuchman, 2001, pp 392)

The advantages of gene therapy can be appreciated from every aspect and in the various organs that it is applied. Among the various organs, the skin has achieved increased interest among genetic researchers as the skin has many capabilities of healing itself. Skin can also produce many substances that are necessary for the various healing processes of the body. Therefore, this is the first area in dermatology where gene therapy is currently working.

With this technology, the skin can be made to produce a variety of therapeutically effective substances that can be used in other therapeutic interventions. (Hengge, 1999, pp 419) Skin is a very good detoxifier and can act as a metabolic sink. Skin especially has the capability of producing immunity-related products that are being widely cultivated through genetic therapy. (Hengge, 1999, pp 420)

Through gene therapy, the researchers are now able to achieve improved transduction rates by pseudotyping, which can help in target cell recognition, in bicistronic expression, can help in reducing the immunogenicity of virus vectors and can help in phenotypic correction of various diseases. (Hengge, 1999, pp 420)

Another area where gene therapy is showing its efficacy is in the relief of various treatments such as chronic pain conditions or arthritis etc. This particular therapy is working by stimulating the painkilling effects of opiates which are commonly prescribed in such patients. This therapy is in many ways superior to other medications, which can cause sleepiness or other side effects with limited efficacy in reducing pain. This therapy has been able to provide pain relief for more than 3 months in the patients studied with higher satisfaction levels. This therapy, therefore, may also be useful for chronic pain conditions such as cancer (Science Daily, 2008, np)

Role of Targetted Gene Therapy in Various Immunodeficiency Disorders

Immunodeficiency states and diseases have long been treated symptomatically. As such, there has been no particular therapy that could cure such patients. Most of these patients had a very short life span characterized by multiple and recurrent diseases and infections. (Mackiewicz, 2001, pp 200) The introduction of stem cell research in gene therapy has been very effective in the severe combined immunodeficiencies. Immunodeficiency states have been successfully treated with various genetic therapies. It was very difficult in the initial stages of the therapy because of a lack of knowledge about various gene functions. With gaining knowledge in this area, it is now possible to treat the correct gene and rectifying it.

Hematopoeitic stem cell research is one of the most contributing areas in this research, and new techniques such as gene transfer may help in improving the outcomes. (Mackiewicz, 2001, pp 204) These cells are mostly used in gene therapy due to their ability to constantly renew themselves, thereby improving themselves. These cells also retain the ability to differentiate themselves into various populations. However, there are certain technical difficulties currently being encountered in the HSC. For this purpose, the first challenge concerned is to improve the engraftment of the cells. Mostly the aim is to purify the transduced cells from the competitors.(Hossle, Seger and Steinhoff, 2002, pp 89)

Cell surface marker genes can be introduced into the cell cultures, which would then express themselves on the successfully transduced cells. These cells can then be selected and introduced in the patients, making the probability of successful treatment higher. However, the human experiments seriously flaw at this point since the selection of the transduced cells may, in fact, result in grafts that are unable to support normal hematopoiesis. There are now clearer concepts about the type of grafting to be used as well. For example, it is now known that “engraftment is dependant on the ratio of the host to donor HSC but not on any actions in the clearing space”.(Hossle, Seger and Steinhoff, 2002, pp 89)

Earlier on, it was thought that HSC niches must be cleared for successful chances of engraftment. These and many other concepts are now being changed as more information is gathered, signifying that genetic therapy still lies in its infancy stages. (Hossle, Seger and Steinhoff, 2002, pp 90)

Potential of Gene Therapy in the Treatment of Cancer

Cancer therapy stands to benefit the most from gene therapy. It stands to have more potential than inherited disorders have from gene therapy. However, there are certain challenges that cancer therapy has. These include the inability to equally distribute genetic material into the whole of the tumour mass. Understanding the various aspects of cellular multiplication and biological activities is of help.

However, the simultaneous requirement is for the development of good vectors for the proper delivery of the genes. Among the most common therapies used in cancer treatments are the suicide genes. Suicide genes include coding for particular enzymes which modify “a non-toxic pro-drug into a toxic molecule, thus leading to the death of the cells expressing the suicide gene” (Kouraklis, 1999, pp 674).

The conditions for which this treatment is being given include malignant mesothelioma, brain tumours, ovarian cancer, metastatic colon cancer, malignant melanoma, and breast cancer. Another treatment in wide use is tumour suppressor gene therapy and oncogene inactivation. This therapy is being used for head and neck squamous cell carcinoma, hepatocellular carcinoma, breast cancer, acute leukaemia and lung cancer, and primary and metastatic liver cancer. Immunogene therapy has shown promise against metastatic ovarian cancer, brain tumours, malignant melanoma, renal and squamous cell carcinomas, and breast cancer. (Kouraklis, 1999, pp 676)

However, for any progress in the field of cancer and its treatment, there is needed constant understanding about the various processes of cancer and how these are genetically influenced and controlled. There are still questions about the direct introduction of genes into the nuclear DNA or whether there should be an extrachromosomal gene transfer system. Tumour suppressor genes are currently being used for the treatment of a variety of cancer, and more research in this area is needed. Since viral vectors are an important mode of transfer of the genes, there is a need for further research and development in the area. The aim is to reduce the toxicity of these viral vectors and increase the transduction efficiency of the non-viral vectors. (Kouraklis, 1999, pp 680)

Genetic Therapy and Osteology

Current orthopaedic surgeons are also looking into the possibility of regenerating the disc tissue in the bone structure of old patients and those suffering from such disorders. Gene therapy, therefore, is being researched in the areas of disc regeneration by knowing the basic fundamentals of disc formation. It is known that disc tissue is made from chondrocytes which synthesize proteoglycans and collagen type II. By improving their production, there is hope that disc degeneration can be achieved successfully. For this purpose, viral vector gene therapy is used, which incorporates TGD beta 1 into the DNA. (Vaccaro, 2006, pp 449)

This gene has the capability to stimulate the formation of proteoglycan and collagen synthesis. A dose dependant response has been learned, and multiple uses of growth factors and affecting genes have shown enhanced results. The introduction of the Sox-9 gene as a promoter of chondrogenesis is also helping in the advancement of the technology. However, there are certain challenges in this area as well. For example, while the growth factors may be successful in slowing the degeneration process, they may not reverse it, bringing to question the possibility of regenerating disc tissue. However, even so, the development is good news for patients, who may not need frequent surgeries for disc replacements etc. (Vaccaro, 2006, pp 449)

So Is Targetted Gene Therapy a Fact or a Fiction?

In many ways, the fictitious nature of gene therapy is present, as it opens up to us the options of cures for all ills. Now there is hope that even the most deadly of medical conditions such as cancer and HIV etc. can be cured. With increased knowledge in the various disciplines of the human cellular mechanisms, there is an improved understanding of how gene therapy may provide answers to questions that were never known.

However, many facts still place the researchers in doubt about the practical implications of genetic therapy. For example, genetic therapy is still in its infancy stages, and there is a lot to be known about the advantages and disadvantages of various procedures before any attempt should be made on human subjects. These attempts are, however, being made, and critics still caution against using these new therapies. Therefore, genetic therapy is currently both fact and fiction since for fiction to become a reality, time is required.

References

Janet E Carter and Edward H Schuchman, 2001. Gene Therapy for Neurodegenrative Diseases: Fact or Fiction? The British Journal Of Psychiatry 178:392-394.

Hengge UR, Taichman LB, Kaur P, Rogers G, Jensen TG, Goldsmith LA, Rees JL, Christiano AM. How realistic is cutaneous gene therapy? Exp Dermatol 1999: 8: 419–431. C Munksgaard.

Johann P Hossle, Reinhard A Seger, and Dirk Steinhoff, 2002. Gene Therapy of Hematopoeitic Stem Cells: Strategies for Improvement. News Physiological Sciences, Vol. 17, No. 3, 87-92.

Human Genome Project Information, 2007. Gene Therapy. Web.

Gregory Kouraklis, 1999. Progress in Cancer Gene Therapy. Acta Oncologica, Vol 38, No. 6, pp 675-683.

Andzej Mackiewicz, Maciej Kurpisz, and Jan Zeromski, 2001. Progress in Basic and Clinical Immunology.

Mount Sinai Hospital / Mount Sinai School of Medicine. “Targeted Gene Therapy Provides Relief For Chronic Pain, Study Shows.” ScienceDaily 2008. Web.

T Niidome and L Huang, 2002. Gene Therapy Progress and Prospects: Non Viral Vectors. Gene Therapy, Vol 9, No 24, pp 1647-1652.

Rovephoenix, 2005. An Overview of Gene Therapy. Web.

A R Vaccaro, 2006. Disc Regeneration: Is It Fact or Fiction? Journal of Bone and Joint Surgery, British Volume Vol 88B Issue SUPP_III, 449.

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