Critically appraise the current progress in gene therapy research

Critically appraise the current progress in gene therapy research

Critically appraise the current progress in gene therapy research


It is a well-documented fact that by the vigorous improvements of science and successive approaches taken by the scientists and medicals for the understanding and management of diseases has increased the life expectancy of some patients. For various reasons, despite considerable progress, gene therapy practice remains rather insufficient when it comes to human beings, hence ethical issues. However, a recent breakthrough has been achieved with respect to an effective restoration of inherited eye sight problems in children, caused by faulty gene called RPE65 which stops the layer of cells at the back of the eye from working. Treatment is carried out by replacing the defective gene and restore function to a part of the body affected by a genetic disorder. Furthermore, another ground-breaking treatment in patients with Severe Combined Immunodeficiency (SCID) has proved success in gene therapy. Gene therapy could be a better solution and a promising approach for effective treatment of some types of cancer, Parkinson's disease, cystic fibrosis, Alzheimer's and other inherited illnesses. This paper reviews the current statues and progress of gene therapy research for the novel treatments of the genetic disorders.

Individuals are unique, the genetics and inheritance that are carried through generations have created the diverse ways in which every person look and behave.

Each individual's genetic makeup is as a result of the effect of mixing and shuffling during the sexual reproduction. Therefore, one could be carrying half of a dozen defective, really "bad" or abnormal genes (Kelly 2007). The carriers are probably blissfully unaware of this fact; until a defective gene being passed to one who is among the millions that experiences the genetic disease.

Until recent progress in medical and scientific approaches, little help was provided to individuals with inherited diseases. However, with the advent of the successful contemporary gene therapy experiments has provided ground-breaking treatments and paved the way for millions of genetic sufferers around the world, despite the setbacks at the beginning of gene therapy treatments (Cideciyan et al., 2009).

Genetic diseases may be treated by the introduction of wild-type gene into the cells affected by a mutation (Cideciyan et al., 2009, Sudbery 2002). This method is called gene therapy. This approach attempts to treat genetic disorders at the molecular level by correcting what is wrong or abnormal with defective genes (Brown 2006).

Statistics reveal that about one in ten people has or will develop a genetic disease at some point in life. In 1983 Victor McKusick, Professor of Medical Genetics at Johns Hopkins University, USA, estimated that between 2,000 to 3,000 genetic disorders can be traced to specific genes. According to current researchers approximately 2,800 of the genetic diseases are caused by defects or mutation in just one of the patient's genes (Kelly 2007).

Gene therapy, a rapidly growing field of medicine, aims to supplant a defective mutant gene with a gene that works. Gene therapy still remains at its infancy level but some successful treatments revolutionised a promising approach to correct the hereditary disease-causing gene in patients but the challenges may be greater than anticipated (Lewis 2005, Alberts 2004, Cideciyan et al., 2009).

Looking back in terms of understanding the biology of cells, the genes and life as a whole; advances in technology has been extraordinary. A whole new approach in terms of different types of gene therapy has enabled the molecular medicine to generate treatment for inherited diseases (Lewis 2008). This new approach for developing therapies could have not been imagined 30 years ago. The early successes of gene therapy treatment were focused on the monogenic diseases such as adenosine deaminase deficiency (ADA), cystic fibrosis, etc. However, most currently the development of the approved gene therapy works concern the treatment of cancer (Kaneda 2001, Kerr and Mule 1994, Lewis 2008).

Like any new medical practice or technology, early success of gene therapy experienced major setbacks. Nearly a decade ago, eighteen year old Jesse Gelsinger was treated for inborn error of metabolism called ornithine transcarbamylase deficiency (OTC) (Sudbery 2002). Unfortunately Jesse Gelsinger died due to an overwhelming immune system reaction against the DNA used to correct the mutated gene. Although Gelsinger's death is a tragedy, gene therapy may be the only hope for (OTC) sufferers, and families of the patients hope Gelsinger's death won't prevent future research (Relph et al., 2004, Lewis 2008, Lewis 2005).

Moreover, before the case of J. Gelsinger early successes such as Laura Cay Boren 1982 and Ashanthi DeSilva late 1980s, who were suffering from severe combined immune deficiency (SCID) (Qasim et al., 2009, Lewis 2005) due to adenosine deaminase (ADA) deficiency, elucidate that the gene therapy approach can be a success and a more effective treatment for millions of patients (Lewis 2008, Michels 2002). However, these were early successes and setbacks of gene therapy era; the main focus of this review is about the contemporary progress of gene therapy, and shall be discussed in more depth.

As technologies and protocols were developed, it became possible that many acquired diseases could be treated by gene therapy (Bonini and Gansbacher 2009). Edelstein et al., 2007 suggested that currently more than 60% of ongoing gene therapy clinical trials are designed to treat different types of cancer and over 1340 gene therapy clinical trials have been recorded worldwide. Gene therapy in cancer is based on the transfer of genetic material to cancer cells to alter a normal or abnormal cellular function (Kyritsis et al., 2009, Bonini and Gansbacher 2009). To exemplify one of the current progresses in gene therapy, Kyritsis et al., 2009 method of delivering the normal gene involved modified viruses to act as carriers to the cancer cells. This method of transformation of vectors was successful in vitro and in vivo. However, Kyritsis et al., 2009 elaborates further that despite the success of transfer of the genetic material to cancer cells, insufficient results has been obtained with human cerebral gliomas (tumour that occur in the region of the brain or spine). Furthermore, this limited finding could suggest that the vector that was used as a vehicle as a means of modifying the abnormal gene was not successful, therefore, effective transfer vehicles will be required to advance this technique.

For purposes of argument it will be necessary to speculate that by simply adding a normal copy of the gene will not necessarily solve the problem ( In fact such gene could pose all sorts of improbable things. This argument illustrates that if a mutated gene encodes a protein that precludes the function of the normal protein from working, the insertion of a normal gene won't help. As far as the normal and mutated gene is concerned, the two are cooperating units. The mutated genes that act in a way that produces a mutated protein in order to affect the normal activity of a functional protein is known as dominant negative mutation. The aforementioned content above as well as the following paragraphs is the touch stone to the development of new progresses involved in gene therapy, and shall be discussed in more details.

Widespread uses of dominant negative mutation became possible with the advent of gene cloning and DNA technology (Brown 2006, Michels 2002). A dominant negative mutation is one that disrupts the activity of the wild-type allele. In the case of a dominant negative fashion, a mutated gene could either be repaired or get rid of it all together (

The diagram below (Fig.1) illustrates in a simplified way the dominant negative mutation, involving the mutated gene resulting in the expression of normal and mutated protein.

To clarify (Fig.1) the Cdc28 protein is a noteworthy example. The Cdc28 protein is a cyclin-dependent protein kinase and binding of proteins called cyclins is necessary to activate the kinase activity of Cdc28 protein. Therefore, Cdc28 is an essential protein needed for the progress from G1 to S and G2 to M in the cell cycle (Morgan 2007, Michels 2002, Alberts 2004). Cyclin proteins are present in limiting amounts at certain times in the cell cycle and if these are depleted the cell will be unable to enter the S phase or mitosis. If a mutation is introduced into cdc28 at a site encoding an essential residue of the kinase activity, such as in the ATP binding site, then the encoded protein will be inactive as a kinase and the mutation will be recessive. However, the ability of the changed Cdc28 protein to bind cyclin has not been affected by this mutation. Therefore, if this mutant cdc28 gene is overexpressed, the mutant protein product will be very abundant and the cyclin proteins will bind to this non-functional protein instead of to the much less abundant wild-type Cdc28 protein encoded. Therefore, the mutant product blocks the activation of the wild-type Cdc28 protein thereby preventing it from functioning (Morgan 2007, Alberts 2004).

Furthermore, in the past few years, substantial efforts have been undertaken to improve and advance these new approaches to gene therapy. Besides the dominant negative mutation, Triple-helix-forming oligonucleotide gene therapy (Castro and Lowenstein 2006) is a method of delivering short, single-stranded pieces of DNA (oligonucleotides)(Qasim et al., 2009). Oligonucleotide bearing sequence complementarily to the chromosomal target is annealed to the specific site forming a triple helix at regions that are rich in purines or pyrimidines (Castro and Lowenstein 2006); refer to (Fig.2).

The third new technique in gene therapy is proposed to be antisense gene therapy. This approach involves in shutting down a mutated gene in a cell by targeting the mRNA transcripts copied from the gene (Kelly 2007). Genes are made of two paired strands of DNA (Lewis 2005). During transcription, the sequence of one strand is copied into a single strand of mRNA, which is called the sense strand in that it has the code to be read for making the protein (Kelly 2007). The opposite is called the anti-sense strand. Procedures to perform this therapy involve delivery of an RNA strand containing the antisense code of a mutated gene and binding the antisense RNA strands to the mutated sense mRNA strands, preventing the mRNA from being translated into a mutated protein (Strachan and Read 2004), as shown in (Fig 3.)

The final contemporary approach in the new advancements is ribozymes gene therapy. The purpose of this therapy like the antisense is to turn off a mutated gene by targeting transcripts copied from the gene, therefore, preventing the production of the mutated protein. This is because ribozymes are RNA molecules that act like enzymes, serving as scissors to cut RNA (Kelly 2007). The ribosomal gene therapy approach is illustrated in the diagram below (Fig.4).

In addition to these fundamental approaches in gene therapy, the methods are still controversial in experimenting or even carrying it out on human patients. This is due to reliability in the motif of gene therapy, efficacy, or the chance of manipulation to the person's gene. These limitations has raised many ethical issues concerning the patient's well-being, self-consent, and government involvement in imposing regulations on the different types of gene therapy, particularly germline gene therapy (Strachan and Read 2004, Sudbery 2002). However, the perspective novel techniques mentioned earlier appear to promise a real revolution in the paradigm of gene therapy. Animal experiments on genetic inheritance diseases are widely used to test new therapies using viral vectors (Kyritsis et al., 2009).

It can be concluded that with current speed of progress in technology, molecular medicine and great understanding of human genome than ever before will bring changes drastically in the way gene therapy is carried out. Perhaps in the coming decade many of the clinical entities, practices and experimental procedures as well as the therapeutic options of today will dramatically disappear. Beside the new approaches evolved for gene therapy, a new era of gene therapy will emerge to the clinical practice towards a more individualised, in other words, on humans. Potential gene therapy for sickle cell disease is already working in mice. Inevitably, such major step forwards in practice will eventually enable to practice gene therapy on humans and cure most of the genetic illnesses. One can be skeptical about this, but considering the early stages of medicine, a dramatic change has been experienced which totally has reshaped the way medicine is practiced today. Early success in gene therapy has pushed the use of different therapies to a different phase and sooner than later the treatment will become available to correct the abnormal gene in human patients.

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