[BojanaL]

What are the main obstacles of gene therapy?

Idea that genes could be used for therapeutic purposes is old; term in coined back in 1972. FDA approved first gene therapy experiment in humans in 1990. However, even with all the promises this therapeutic approach may have – it doesn’t evolve as quickly as we might hope.

It all started with experiment on 4 year old girl suffering from the adenosine deaminase deficiency and severe combined immunodeficiency disease (ADA SCID). This is extreme type of immune system disorder where both T and B cell lymphocytes fail to develop properly and as a result body can’t fight even the slightest infection. Usual treatment for ADA SCID is bone marrow transplantation and it needs to match perfectly (must be donated by the close relative). Mutated gene responsible for sickness is located on the X chromosome (IL2RG). In the mentioned experiment, T cells were extracted from her blood, normal copy of the ADA gene was inserted in the T cells, and they were brought back to the body. Result was normalization in the T cell number, but girl had to continue receiving gene therapy to ensure appropriate working of the immune system in the future. This experiment showed that gene therapy could be a possible solution for the severe disorders. With the initial success, gene therapy using viral vectors carrying healthy gene start applying to a bigger number of patients, but it was soon discovered that viral vector used in the study could induce expression of some other genes beside expected one. Insertion of corrected gene triggered a nearby oncogene resulting in leukemia in a lot of patients. Before discontinuation due to serious side effect, this therapy managed to restore immune system in 17 children.

Besides having questionable viral carriers that might trigger other than expected genes, few other problems exists as well. Virus can target wrong cell. If used to treat cancer and skip invading the right cell or appropriate DNA place, it can produce even more damage by accelerating tumor growth, for example. Sometimes, even if right cell and part of DNA is targeted – gene expression could fail or it can produce unexpected effect. Virus used for cystic fibrosis treatment produced immune response even when inserted in the right place. Also, cells need to divide frequently so the viral vector could insert and express gene efficiently. Bone marrow cells are not undergoing as much cell divisions as needed and as a result they can’t be genetically altered always.

There are also some ethical issues associated with gene therapy. Not all genetic diseases are obvious. If you decide to test yourself, you may discover disorders that could place you in a high risk group that will inevitably affect all aspects of your life - from employment to the health insurance. With people planning a family, option to test your future offspring may result in increased abortion rate since genetic testing could show abnormalities that normally wouldn’t be seen. But it might help parents that are familiar with their altered genetic status to prevent having children with the same genetic disorders. Other than that, what genetic abnormality would be considered important and worth of healing? Which one would have higher priority? Like genes responsible for diseases, other could be responsible for good looking (beauty), and genetic therapy could easily become a tool in cosmetic industry and skip research in the field where is more important.

There are a lot of challenges gene therapy needs to overcome. Most illnesses could not be eradicated easily and long lasting treatments are inevitable part of the gene therapy. Immune system is responding any time vector is inserted. Viral vectors are not always precise in targeting certain cells or part of DNA. Some disorders are result of multiple dysfunctional genes and it’s hard to design a vector that could improve all of them. Vectors could result in disease aggravation or oncogenesis if not inserted properly.

It may sound that negative aspects are dominating, but for the past 5 years gene therapy showed increased success in healing Leber's congenital amaurosis, adrenoleukodystrophy, chronic myelogenous leukemia and Parkinson's disease. It needs to be improved, but with modern techniques it’s just a matter of time.