18 November 2009

Gene therapy: successes, difficulties, prospects

Judging by the recent revival of work in the field of gene therapy, this science seems to be starting to move out of the shadow of laboratory experiments on the path of promising prospects.

The current autumn turned out to be especially rich in fateful developments: scientific journals reported several important achievements in the field of gene therapy at once. So, with the help of viral delivery of the gene responsible for the formation of the visual pigment of the retina in an experiment on saimiri monkeys (squirrel monkey) with congenital color perception disorder, it was possible for the first time to restore the ability to distinguish between red and green colors in animals, which gives hope for the possibility of using this method for the treatment of color blindness in humans. Transplant scientists also did not lag behind their colleagues and, in turn, showed that they had learned to improve the condition of donor lungs by activating a gene encoding the synthesis of anti-inflammatory molecules. Even fatal brain diseases will now have to retreat before the possibilities of gene therapy that have opened up. Scientists managed to stop the development of adrenoleukodystrophy in two boys by resorting to the help of a modified HIV to deliver the gene responsible for the synthesis of the missing enzyme.

Adrenoleukodystrophy (melanocutaneous leukodystrophy, Addison-Schilder disease) is a degenerative disease of the white matter of the brain. The type of inheritance is recessive, linked to the X chromosome. This disease, caused by a defect in an enzyme involved in the metabolism of fatty acids, leads to a failure of the function of the adrenal glands – the endocrine glands that produce vital hormones.

And finally, an equally serious problem of muscular dystrophy has also been reflected in research. A recent paper reports that monkeys with myodystrophy caused by gene damage managed to achieve an increase in muscle volume and strength after injecting a healthy copy of the desired gene into their cells. Researchers believe that such a method will soon be able to come to the aid of patients with degenerative muscle diseases.

Mark Kay, director of the Human Gene Therapy Program at Stanford University Medical School, is quite satisfied with the recent successes of his colleagues. According to him, researchers working in the field of gene therapy are more optimistic than ever.

Is optimism justified?Despite the significant successes of gene therapy, scientists still face many obstacles that will have to be overcome on the way to the clinical application of their developments.

Recent works have rendered an invaluable service to strengthen the position and demonstrate the prospects of gene therapy. Now scientists working in this field are full of optimism and, judging by the results, their methods will soon really work in practice. A distinctive feature of genetic research is a lot of unforeseen difficulties, but nevertheless, in a fairly short period of time for science in 30 years, significant progress has been achieved.

Already, we can name a number of diseases for which gene therapy methods can be the ideal, if not the only, solution. The simplest example is disorders such as adrenoleukodystrophy or degenerative changes in the retina, when it is necessary to correct the function of only one gene in a small number of cells.

There are, however, other diseases caused by a violation of one gene, but more difficult to treat. For example, Duchenne muscular dystrophy requires correction of only one gene, but in order for the results of treatment to be successful, the defect must be corrected in almost all muscle cells in the whole body. It is also not easy to cure cancer with the help of gene therapy, in which it is necessary to find a lot of malignant cells, often not localized in a solid tumor, but spread over various organs and tissues, but probably in combination with other methods, gene therapy can provide a good therapeutic effect.

Experts identify four main difficulties that need to be overcome on the way to the clinical application of gene therapy methods.

1) First of all, it is necessary to obtain a vector specific to this type of cell (virus, nanoparticles, etc. delivery means) in sufficient quantities to achieve the result and not dangerous to the cells themselves.

2) After the vector with the genome included in its structure reaches the desired cell, it must penetrate inside and reach the nucleus. Solving this problem turned out to be more difficult than expected. Usually, there are many barriers in cells that prevent the interaction of new DNA with the cell's own DNA, but viruses have evolved mechanisms to bypass these obstacles, and therefore are considered the best tools for gene delivery.

3) Once embedded in the nucleus, the new gene must remain stable for a certain period of time. It is not uncommon for a cell to block a new gene, making it ineffective.

4) And finally, the most serious problem is a possible immune response: the body can reject a vector or a "foreign" protein encoded in the therapeutic gene.

Another common problem is determining the time during which the effects of gene therapy should persist. In the case of infection or cancer control, the therapeutic effect continues until the infection or cancer cells are completely destroyed. But in the case of genetic disorders, gene therapy courses in most cases need to be repeated throughout life.

The reverse side of the coin

A person tends to be cautious about everything new. In the case of gene therapy, it is also impossible to predict for sure what pitfalls this method may conceal. For example, more and more evidence suggests that patients can get very specific problems. In 1998, an experiment was widely publicized, as a result of which ten children managed to cure X-chromosomal severe combined immunodeficiency (TCID) using gene therapy. Later, however, two of them developed leukemia. Each case of inclusion of new DNA in a cell is accompanied by an increased risk of developing malignant neoplasms. Delving into the little-studied field of gene therapy, it is important not to lose sight of delayed side effects.

The limits of what is allowed

Serious ethical discussions are likely to appear in the future, when the time comes to decide for what purposes to use gene therapy methods. There is no doubt that gene therapy should be used to combat severe mental disorders or genetic diseases, but the idea of using such methods to treat behavioral disorders, whether depression or drug addiction, raises justifiable doubts. Is it possible to use gene therapy in in vitro fertilization so that the child is born not with destined destiny, but with certain character traits, high intelligence or athletic abilities of the parents? Even if something like this seems fantastic now, with the development of gene therapy, such questions will certainly arise.

Horizons and prospects

While the main direction of research in the field of gene therapy remains the introduction of functional genes into the body, one of the promising ways may be the development of active molecules capable of "turning off" defective genes. For example, in the case of Huntington's disease, with the help of gene therapy, defective genes encoding the synthesis of abnormal proteins can be turned off.

An important aspect of all such diseases is treatment at an early stage, before the pathological process spreads to healthy tissues. Preventing the disease is much more effective than fighting the irreparable consequences inflicted on the body as a result of the development of neurodegenerative diseases or muscular dystrophy.

Ruslan Kushnir
Eternal Youth Portal www.vechnayamolodost.ru based on the materials of The Scientist: Q&A: Gene therapy turnaround


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