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Gene Therapy Is Finally Becoming a Medical Reality

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Gene Therapy Is Finally Becoming a Medical Reality

Protocol for Ex Vivo Gene Therapy

National Human Genome Research Institute

What is Gene Therapy?

Right from the start of genetic engineering in the early 1970s, biomedical researchers had the idea of surgically replacing a defective gene with a functioning one to cure a genetically inherited disease. Initially, more science fiction than science, it took 10-15 years for scientists to really begin testing ways the developing techniques in genetic manipulation might make such a gene substitution possible.

In 1984 researchers at Scripps and UC California in San Diego introduced a functional gene for hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in white blood cells from patient that had Lesch-Nyhan disease where this gene is defective. While this work was only done in the lab and the cells were not used to treat the patient, this study was the first to show that an inherited genetic defect could be corrected by adding a new version of the gene with the right DNA sequence.

The next year, 1985, Drs. W. French Anderson and Michael Blaese at the NIH used the same technique to successfully replaced the adenosine deaminase (ADA) gene in cells from a patient with congenital adenosine deaminase deficiency—a rare but serious illness that compromises the immune system.

Four years later, in 1990, they took the next step and put treated cells back into a patient, 4-year-old Ashanti de Silva who suffered from this genetic disease, and cured her. This was the first use instance of human gene therapy and it appeared to be safe and effective.

Gene Therapy Fervor

With such amazing initial success, momentum grew quickly and gene therapy trials started up all over the US and Europe. However, real successes remained elusive throughout the 1990s. It was proving more difficult to introduce new genes into humans, and even often in animals, than anticipated.

There were a number of challenges that the current state of the art in gene transfer technology was not up to meeting. Many aspects of gene regulation were poorly understood, and patient inflammation and immune responses complicated delivery. Remember, this was all occurring before the completion of the human genome sequence. However, trials to treat diseases such as cystic fibrosis, HIV infection, various cancers, and Gaucher's Disease continued .

The Big Gene Therapy Set-Back

With any new technology, many things can go wrong and, in 1999, a tragic turn of events interrupted the rapid advance of this new area of medicine. At the University of Pennsylvania, Jesse Gelsinger died as a result of a severe immune response to the modified adenovirus-derived vector he received which carried into his cells the gene for an enzyme he lacked to metabolize ammonium.

The test was really designed to just confirm the safety of the therapeutic approach for children born with the same disease. Later investigation would show that impropriety on the part of the doctors who covered up some data indicating the treatment was more risky than Jesse Gelsigner and his family was lead to believe.

Around the same time in France, bone marrow cells from infants born without an immune system (i.e., bubble boy syndrome) were infected with a retrovirus carrying a function version of the IL2RG gene needed to trigger an immune response. The treatment cured most of the children (10 out of 11). However, the retroviral vector disrupted the genes surrounding the place where the new gene inserted in the DNA, and 4 of the cured children developed leukemia; one subsequently died.

Another child also developed leukemia as a result of similar trials a couple years later in London. As a result of these events, it was clear more caution was needed before proceeding with human gene therapy trials. Other concurrent gene therapy trials stopped and new planned trials were held up.

Finally Realizing the Potential of Gene Therapy

Although several of the children treated for bubble boy syndrome developed leukemia, the gene therapy did cure the disease. Basically, the procedure worked, albeit with unacceptable side effects in some cases. As a result, research continued and, over the last decade, the tools to manipulate DNA and our understanding of the human genome has advanced considerably.

Several recent successes in gene therapy treatments have produced a lot of optimism that practical treatments for some diseases may soon be approved. For example, in February of this year, researchers at the University of Pennsylvania completed a follow up trial using gene therapy to correct a defective retinal pigment RPE65 gene that causes Leber congenital amaurosis (LCA) blindness. This is currently the most advanced gene therapy trial, having been ongoing for more than 7 years and, barring unexpected results, will likely to be first FDA approved gene therapy procedure.

At the end of 2011, a group from the University College of London also announced the first successful treatment of4 patients with hemophilia B with an insertion of a functional version the gene for clotting factor IX gene. Also, following up on a 2009 trial by researchers in France that cured 2 boys with adrenoleukodystrophy, a fatal genetic brain disease, studies are in progress to use gene therapy approach to treat more common brain disorders such as Parkinson's, and multiple sclerosis.

The promise of gene therapy that so excited the medical community over 20 years ago seems on the verge of being realized.

(First posted: May 7, 2012)

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