Gene Therapy: History, Types And Challenges

Introduction

Gene therapy typically involves the insertion of a functioning gene into cells to correct a cellular dysfunction or to provide a new cellular function. For example, diseases such as cystic fibrosis, combined immune deficiency syndromes, muscular dystrophy, hemophilia, and many cancers result from the presence of defective genes [1].

Gene therapy is basically to correct defective genes responsible for genetic disorder either by insertion (most common), homologous recombination, through selective reverse mutation, or by altering the regulation of a particular faulty gene [2,3].

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History of gene therapy

It is difficult to pinpoint the beginning of gene therapy, but 1967 can be considered as the beginning of at least the discussion about gene therapy. Marshall Nirenberg, who won the Nobel Prize in physiology in 1968, wrote in a 1967 paper about “programming cells with synthetic messages,” recognized the usefulness of this procedure but also discussed its potential pitfalls and dangers.

In 1980 the first attempt of applying human gene therapy was conducted by Martin Cline at the University of California, Los Angeles (UCLA). Without obtaining approval from the UCLA IRB and the other regulatory bodies, Cline performed a recombinant DNA transfer of the beta- thalassemia gene into bone marrow cells of two patients with beta-thalassemia, in Italy and Israel [4]. Since 1989, more than 900 clinical trials have been approved worldwide [5].

In 2003 as well as in 2005 China approved the first gene therapy drugs. A first European application for the approval of a gene therapy drug for the treatment of an aggressive brain tumor was submitted to the European Agency for the Evaluation of Medicinal Products (EMEA) in 2005. Despite continued great difficulties, the successes of gene therapy can doubtlessly be confirmed today.

Types of Gene Therapy

Gene therapy can be organized according to its cellular target, into two types, somatic gene therapy and germ line gene therapy. In somatic gene therapy, the somatic cells of a patient are targeted for foreign gene transfer. In this case the effects caused by the foreign gene is restricted to the individual patient only, and not inherited by the patient's offspring or later generations [6]. In the germ line gene therapy germ cells (sperm or egg) are modified by the introduction of functional genes, which are integrated into their genome. Therefore changes due to therapy would be heritable and would be passed on to later generation [7].

Gene delivery

Gene delivery systems can be classified into two broad categories: non-viral physicochemical approaches and recombinant viral systems. The comparative strengths of non-viral approaches include ease of chemical characterization, simplicity and reproducibility of production, larger packaging capacity, and reduced biosafety risks [8]. Gene delivery, however, is relatively inefficient and the effects are often transient. Improvements to nucleic acid stability and potency as well as lipid and polymer delivery technology are, however, advancing the field of non-viral gene delivery [9]. Non-viral gene delivery systems generally consist of three categories: (a) naked DNA delivery, (b) lipid-based and (c) polymer-based delivery [10–21]. In contrast, viral systems, which are commonly modified to render them replication incompetent, are markedly more efficient and exploit favourable aspects of virus biology [22–24]. Viral vectors can be divided into two main categories: non-integrating and integrating, based on the intracellular fate of the vector genome. These properties are important when considering the required duration of the treatment. The most commonly used viral vectors are derived from retrovirus, adenovirus and adeno-associated virus (AAV). Other viral vectors that have been less extensively used are derived from herpes simplex virus 1 (HSV-1), vaccinia virus, or baculovirus.

There are mainly two approaches for the delivery of vectors i.e. ex-vivo and in-vivo [25]. The ex-vivo is the commonest method, which uses extracted cells from the patient. The cells are sourced initially from the patient to be treated and grown in culture before being reintroduced into the same individual. This approach can be applied to the tissues like hematopoietic cells and skin cells which can be removed from the body, genetically corrected outside the body and reintroduced into the patient body where they become engrafted and survive for a long period of time. On the contrary, the in-vivo technique involves the transfer of cloned genes directly into the tissues of the patient. This is done in case of tissues whose individual cells cannot be cultured in vitro in sufficient numbers (like brain cells) and/or where re-implantation of the cultured cells in the patient is not efficient.

Challenges in gene therapy

As in other areas of research, validation of new therapeutic methods is closely related to the development of clinical trials, and prior approval by the international ethics committees is, therefore, required. Some types of vectors, notably adenoviral and retroviral vectors, have produced serious and even fatal side effects and, therefore, security seems to be the main obstacle for the application of this type of clinical intervention in hospitals and other public health care centers particularly in under developed areas or countries .

Although modification of germ-line cells at gene level offers the possibility of permanently eliminating certain genetic diseases, important ethical concerns, including eugenics (improvement of human race by selective breeding) and transfer of undesirable trait or side-effects to the patients’ descendents, currently prohibit its development and therefore only somatic gene therapy is in progress. Gene therapy faces numerous challenges including; short-lived nature of gene therapy, problem with viral vectors, immune response, multigenic disorders, and insertional mutagenesis. The future successes of gene therapy depend on the advancements in other relevant fields, such as medical devices, cell therapies, protein therapies and nanotechnology [26-28].

Overall, gene therapies are new procedures that are still in the experimental stage. This is a very risky therapy, since many vehicles are viruses with genetic material therefore, may undergo genetic recombination and become more virulent. From the point of view of bioethics, the main obstacle to the application of RNAi-based gene therapy is the fact that the non-viral vectors are still inefficient or have very limited application. Therefore, studies that evaluate the effects in experimental models and in preclinical trials are needed in order to validate the potential effectiveness of this type of therapeutic intervention. It is necessary to evaluate the actual benefits as well as to detect the potential risks of implementing this therapy so that both safety and human health are preserved, and worse health problems than those we have today are avoided.

References

1. Culver, K. (1994). Gene Therapy—A Handbook for Physicians. Mary Ann Liebert, Inc., New York.
2. Miller DA. Human gene therapy comes of age. Nature 1992;375:455460.
3. Verma IM, Weitzman MD. Gene therapy: Twenty-first century medicine. Annu Rev Biochem 2005;74:711-738.
4. Mercola Ke,Cline MJ. The potential of inserting new genetic information. N Engl J Med 1980;292:1297-1300.
5. Edelstein, M. L., Abedi, M. R., Wixon, J., and Edelstein, R. M. (2004). Gene therapy clinical trials worldwide 1989-2004—an overview.J Gene Med 6, 597-602.
6. Bank A. Human Somatic Cell Gene Therapy 1996;18:999-1007.
7. Mathews QL, Curiel DT.Grne Therapy: Human Gemline Genetics Modifications-Assessing the Scientific,Socioethical, and Religious Issues. Southern Medical Journal 2007;100:98-100.
8. Yin,H.,Kanasty,R.L.,Eltoukhy,A.A.,etal.(2014)Non-viralvectorsforgene-basedtherapy.Nat.Rev.Genet.,15,541–555.
9. Semple, S.C., Akinc, A., Chen, J., et al. (2010) Rational design of cationic lipids for sirna delivery. Nat. Biotechnol., 28, 172–176.
10. Conwell,C.C. and Huang,L. (2005) Recent advances in non-viral gene delivery. Adv.Genet.,53,3–18.