Recent Advances In Gene Therapy Biology Essay


Gene therapy is an advanced technique used in treatment of many inherited and acquired diseases. Gene therapy involves the transfer of a gene into a cell to replace a defective gene. Two methods have been developed for gene transfer; ex vivo and in vivo gene therapy. Many strategies are developed in this field in order to have a successful therapeutic end. Viral transfer; which is the use of viruses as vehicles for gene transfer, is a recent advance in gene therapy. However many complications and risks appeared in this strategy. Future strategies for elimination or reduction of the risks in this technique are under development. Ethics in human gene therapy are taken in consideration in the process of development of new strategies in gene therapy. Gene therapy definition, methods, applications, challenges and ethical considerations are the focus of this review.

Keywords: Gene therapy; ex vivo; in vivo; viral transfer; ethical consideration, inherited diseases, acquired diseases

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1. Introduction:

Gene therapy is a technique used increasingly in treatment of inherited and acquired diseases. Mutations in genes lead to inability of encoded proteins to carry out their normal functions which lead to the development of diseases. These mutated or defective genes can be eliminated by gene therapy. Elimination of these defective genes is by replacement with working genes (Cornetta 2010). Therefore, gene therapy is an evolving field in clinical and medical therapeutics (Wunderbaldinger et al. 2000). Two methods in gene therapy have developed; ex vivo gene therapy and in vivo gene therapy. Ex vivo is the introduction of new gene into a cell outside the body, while in vivo is the insertion of the gene into the cell in patient body (Hanania et al. 1995). Vectors are used as vehicles for gene transfer. Viral and non-viral vectors are used in gene therapy for gene transfer (Atkinson and Chalmers 2010). The first human gene therapy trial was initiated at National Institute of Health (NIH) in 1990 (Wunderbaldinger et al. 2000). Gene therapy have been applied for treatment of many diseases like; Parkinson Disease, Cancer and Ocular disease (Ocular gene therapy) (Farzaneh et al. 1998). However, many complications and risks evolved. New strategies to overcome these problems are developed.

2. Background:

2.1. Definition:

Each individual has two sets of chromosomes, each one inherited from one parent. Genes on chromosomes encode proteins and responsible for protein expression and production. Proteins carry out most of body functions and cellular structures. If any mutation occurs in a gene; either inherited or induced mutation, this mutation will lead to production of non-functional protein, which is unable to perform its function in the body. Deficiency of this protein will lead to disease (Mochizuki et al. 2008a).

Diseases can be cured if the mutated gene is replaced by working or functional gene. Gene therapy is a technique designed to introduce working gene in a cell. It is used to replace abnormal or faulty copy with a working copy of the gene (Cornetta 2010b). Gene therapy is commonly used in medical and clinical fields to treat many inherited and acquired diseases (see Figure 1). A normal gene is introduced into a cell to compensate for disease causing gene and make beneficial proteins. The process of gene transfer is mediated by vectors (Hanania et al. 1995).

Figure1: Diagram showing mechanism of gene therapy, modified from (Atkinson and Chalmers 2010)

2.2. History:

Friedmann and Roblin were the first scientists to publish a paper in gene therapy for human genetic diseases in 1970s. In1990, the first approved gene therapy case took place (Hanania et al. 1995; Mochizuki et al. 2008a). During 1990s, many genetic diseases have been treated using gene therapy. However, side effects appeared later on patients treated. Now many developments are done to overcome this problem. In 2000, gene therapy was used to treat brain disease; Parkinson's disease using viral vectors in animal models (Escors and Breckpot 2010).

3. Vectors and methods of gene therapy:

In gene therapy, there are three methods used to transfer genes. These methods are:

1- Packaging them into a virus (viral vectors).

2- Applying them directly in the form of a plasmid (naked DNA or non-viral vectors).

3- Delivering them directly through physical methods. (Bouuaert and Chalmers 2010)

3.1. Viral vectors:

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Figure2: Gene therapy using adenovirus vector modified from (Atkinson and Chalmers 2010) 3.1.1. Adenovirus: Adenoviral vectors (see figure 2) have a broad range of host cells. Their expression of capsid and proteins lead to immunogenecity (Borrás 2003).

3.1.2. Adeno-associated virus: Adeno-associated viruses have a small genome. They lead to hormonal immune response (Atkinson and Chalmers 2010).

3.1.3. Retrovirus: Retroviral vectors are commonly used in gene therapy (see figure 3). Their random integration might cause insertional mutation (Bouuaert and Chalmers 2010).

Figure3: Gene therapy using retrovirus vector modified from (Bouuaert and Chalmers 2010)

3.1.4. Lentiviruses: Lentiviruses have the ability to infect both dividing and non-dividing cells. Their use is based on human immunodeficiency virus (Escors and Breckpot 2010).

3.1.5. Herpes simplex virus 1 (HSV-1): HSV-1 has the ability to replicate in epithelial cells. Genome size of HSV-1 is large (see table 1) and this enables HSV-1 to accommodate large or multiple transgenes (Latchman 2001a).

Virus vector


Adeno-associated virus

8,500 base pairs


35,000 base pairs

Herpes Simplex virus

150,000 base pairs


10,000 base pairs

Table 1: Genomic size of virus vectors modified from (Latchman 2001b)

3.2. Non-viral vectors:

3.2.1. Naked DNA: Naked DNA plasmid has a large macromolecule weight. It losses its stability once it enters the body because it is susceptible to extracllular and intracellular nucleases (Atkinson and Chalmers 2010;Borrás 2003).

3.2.2. Minimalistic immunologically defined gene expression (MIDGE) vectors:

MIDGE vectors are not commonly used in gene therapy (Borrás 2003).

3.2.3. Cationic liposomes: Cationic liposomes do not elicit cellular immune response. They cause toxicity (Atkinson and Chalmers 2010).

3.2.4. Polyethylenimines: Are extensively used for gene delivery. However, they are considered as toxic polymers (Bouuaert and Chalmers 2010).

3.3. Physical methods:

3.3.1. Electroporation: Penetration of DNA through cell membrane using electric pulse (Wunderbaldinger et al. 2000).

3.3.2. Gene gun: Delivery of DNA with heavy metal to cells using pressure and speed (Wunderbaldinger et al. 2000).

3.3.3. Sonoporation: Penetration of DNA through cell membrane by creating membrane pores using ultrasound (Wunderbaldinger et al. 2000).

4. Recent studies and applications of gene therapy:

Gene therapy represents an exciting and promising technique in clinical medicine and is rapidly evolving field in medical therapeutics. Many studies are done in this field to improve protocols for successful treatment of human genetic disorders. Today, there are more than 200 protocols to perform gene replacement and evaluate the efficiency of gene expression (Mochizuki et al. 2008a). In vivo and ex vivo strategies are used for gene delivery (see table 2). In vivo is the direct administration of the vector to the patient. Ex vivo is gene transfer or genetic modification of cells outside the body (Naegele et al. 2010). In vivo is commonly used for treatment of patient with brain and ocular diseases (Borrás 2003; Mochizuki et al. 2008a). Delivery of gene in vivo is essential to test the effect of overexpressing of a particular gene on biological process and testing gene function in intact animal for human gene therapy procedures (Naegele et al. 2010).


In vivo gene therapy

Ex vivo gene therapy


Direct administration of the gene or vector into the target organ or into patient

Harvesting and cultivation of cells from patients with in vitro gene transfer and reintroduction of transfected cells

Possible target cells

Can be applied to any cell

Lymphocytes, bone marrow cells,umbilical cord blood stem

cells, hepatocytes, tumor cells,

skin fibroblasts


Stable transgene expression can be achieved with appropriate vectors

Therapy can be targeted

May overcome low transfection efficacy with large volume of vector and prolonged exposure


Low transfection efficacy

Delivery of therapy to target cells may be difficult, Concerns regarding safety of vectors

Possible inadvertent transfection of cells other than the target cells, including germ-line cells

Unstable expression of the transgene

Potential for graft rejection

Nonspecificity of the transduced cells

Table 2: Strategies for gene administration modified from (Parra-Guillen et al. 2010)

Recent studies were carried on for applications of gene therapy for cancer (Farzaneh et al. 1998), brain diseases (Hanania et al. 1995) and ocular diseases (Borrás 2003). 60% of clinical gene therapy trials are in cancer. These trials focused in chemogen therapy and immunogene therapy, meaning introduction of genes and modulation of patient immune response (Hattori 2010; Farzaneh et al. 1998). Gene therapy was successfull in treatment of brain diseases; ex. Parkinson's disease (PD). The considerations in PD gene therapy are; what is the target gene and how to deliver that gene (Hanania et al. 1995). After several clinical trials, the protocols for PD gene therapy were approved. The vehicle for gene delivery to the human brain is adeno-associated viral vector (Yang et al. 2007), which is a nonpathogenic and non-self amplifying (Atkinson and Chalmers 2010). Target gene of PD has been identified (Hanania et al. 1995). Many studies in ocular gene therapy (see Figure 4) help in identification the target gene and proper gene delivery method for each type of eye diseases (Mochizuki et al. 2008a). In vivo delivery of exogenous gene to the eye has the potential of treating ocular diseases. Eye is immune-privileged site (Borrás 2003; Mochizuki et al. 2008a).

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Figure 4: Ocular gene therapy- A graphic illustration of an experimental gene therapy being tested to treat a sight disorder modified from (Yeh et al. 2008)

New strategy in gene therapy is suicide gene therapy. Suicide gene will cause a cell to kill itself by apoptosis. Activation of these genes induces apoptosis by p53 protein.

Suicide gene therapy is a potential way of treating cancer or other diseases. This strategy is still under experimentation to overcome limitations and use for treatment of human genetic diseases; ex. cancer (Georgoudaki et al. 2010).

5. Limitations and ethics:

5.1. Challenges in gene therapy development:

Gene therapy is still under experimental control and much research remains to be done before application on human. Many clinical trials have been done on human. However, many problems appeared later leading to setback to gene therapy research. In 1990, the first approved gene therapy was published. It performed on a girl with genetic defects. It left her with immune deficiency system. The effect was temporary but successful. In 2000, gene therapy was used for treatment of a form of immune deficiency (Severe Combined Immune Deficiency). Two of the children treated developed leukemia in 2002 and 2003 (Cornetta 2010b). In 1999, death of a girl in gene therapy experiment resulted in a significant setback to gene therapy research. In 2007, first gene therapy trial for inherited retinal disease was published. The first operation was carried on a male with inherited blinding disease. It yields positive results. The patient's vision increased with no apparent side-effects (Cornetta 2010b).

Challenges in gene therapy development are considered as: choosing of appropriate gene to be replaced, choosing the appropriate method of gene delivery; wither using viral or non-viral vectors, achieving appropriate regulation of gene expression and avoiding side effects (Doering and Spencer 2009). Difficulties in purifying virions, vector toxicity, mutagenesis and immune response to the vector are side effects (Atkinson and Chalmers 2010; Levicoff et al. 2005). Mutagenesis is induced when introduced gene integrate into a coding region in the genome and lead to activation of a cancer-causing gene (Atkinson and Chalmers 2010). Immunogenecity; when the body rejects the introduced cell with the new gene (Yeh et al. 2008). Adenoviruses were developed to be able to grow in large quantity and highly purified (Yang et al. 2007). Recent advances in gene therapy are to minimize immunogenecity and improve efficiency of gene transfer. HSV vectors can be used to test the effects of specific genes on animal models and for gene therapy in humans (Latchman 2001b).

5.2. Ethics:

Gene therapy researches are done on animals first. Animal models were used for testing gene therapy for treatment of PD, cancer, and ocular diseases (Hanania et al. 1995; Bouuaert and Chalmers 2010). Many ethical considerations are in human gene therapy. Safety concerns and capability of transferring mutations resulted from introduced genes must be considered seriously in gene therapy protocols (Persons 2010; Hanania et al. 1995). In human gene therapy, somatic cells must be used because changes in somatic cells can not be transferred to new generations (Naegele et al. 2010).

6. Discussion:

Gene therapy is an advanced technique in treating human generic disorders. Almost all clinical trials are done on animal models. Human gene therapy is not fully successful. Side-effects apparent led to setback of gene therapy. Most gene therapy trials led to other diseases and may death of patients. Many experiments have to be done to reduce magnitude of side-effects. Now all gene therapy experiments are done on animals. Parkinson's diseases, sickle cell, ocular diseases and many other diseases have been treated successfully in animal models but not in human. There was only on case with eye disease that treated successfully without any apparent side-effects. However, we can not consider gene therapy as safe and successful.

7. Conclusion:

Gene therapy is the delivery of specific gene to replace the defective gene. Several methods are used for gene transfer (Cornetta 2010). Gene therapy used for treatment of several human genetic diseases (Mochizuki et al. 2008b). Efficiency of gene therapy was first tested on animal models. Suicide gene therapy is a promising technique to treat human diseases. It is underway and scientists hope to end with acceptable and approved protocols (Georgoudaki et al. 2010). Many challenges and limitations in gene therapy development appeared. Safety concerns and ethical considerations are considered seriously in gene therapy protocols (Persons 2010). At the end, the field of gene therapy is just in its infancy and many studies are needed for development of this field (Cornetta 2010a).