R. Michael Blaese, M.D., Chief, Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health

What is it, and when might it become available?

We have all heard about the possibility that gene therapy could be developed to treat MSUD and other serious diseases that are caused by a defective or misspelled gene. So far that possibility has seemed to be just out of reach. Traditional methods of gene therapy try to take a "normal copy" of the gene that is causing the disease, and deliver it to the cells in the patient's body that are crippled by the defect with the hope that this new "normal" gene will reverse the disease. This treatment has worked in some very special cases where the diseased cells from a patient can be removed from the body and the corrective gene inserted while the diseased cells are growing in a test tube.

Unfortunately, for MSUD and the majority of other serious genetic diseases, the "diseased cells" cannot be removed for treatment in a test tube, and therefore the corrective gene needs to be delivered to the cells where they ordinarily live inside the body - for example, the liver or brain. Most of the traditional ideas for gene therapy have run into this "delivery" brick wall and their development has been stopped at this stage.

Many genetic defects can be thought of as a "typo" that causes the code contained in the gene to be misspelled. Such typos in the spelling of the gene, called mutations, can occur while a gene is being duplicated during cell division or as a result of external factors such as radiation exposure, etc. Since genes are inherited, once a misspelled gene develops for any reason, it has the potential to be transmitted from generation to generation, just as the normally spelled genes are passed on. For many genetic diseases, a misspelling involving only a single letter in a gene that is made up of thousands of letters (or bases) can cause disease. As an "ideal treatment," physicians would like to have tools to correct the typo in the spelling of the gene in those cells in the body where that genetic defect is causing a problem.

Recent research at Kimeragen, a biotechnology company, has led to the discovery of a way to correct, or mutate, the spelling of a gene directly in the cells of the body. Now, rather than needing to replace an entire gene that does not work, because just one letter out of the thousands in the gene is misspelled, it will be possible to treat genetic disorders with a much simpler idea - gene repair. This new gene repair technology is very different from the usual pharmaceutical product, because it uses a small molecule that is custom designed and produced for each individual or family in order to correct the unique gene defect that is found in that family. The molecule, called a chimeraplast, is a combination of both DNA and RNA sequences that direct the body's own molecular tools used to repair genes in order to change the defective gene sequence to a normal sequence. To test the feasibility of this idea, rats with inherited genetic defects affecting the liver have been treated using a simple intravenous infusion of a chimeraplast which was specifically designed to correct their mutations. Because early results in two different genetic disorders in rats have shown such promising results, active plans are now underway to begin treating an inherited human disease of the liver, called Crigler-Najjar syndrome, beginning next summer.

Is this a treatment that could be used in MSUD, and when might it be available? Theoretically, many (but probably not all) of the mutations leading to MSUD should be correctable using this new technology, but no work has been done yet to actually test mutations from different MSUD families.

Kimeragen plans to develop this new treatment for patients with many kinds of genetic defects involving the liver including MSUD, PKU, OTC deficiency, hypercholesterolemia, hemophilia, etc., etc. When treatment will become available for each of these diseases will depend on the success of early human clinical trials in Crigler-Najjar patients, as well as cooperation from the FDA in helping move this treatment from the experimental trials to general availability. Also, Kimeragen is a small company with limited resources. We are working to establish partnerships with larger pharmaceutical companies in order to fund more rapid development of this treatment for a broader range of diseases. If the early clinical trials show promise, clinical trials testing this treatment in MSUD could begin sometime in 2000 or 2001.

Dr. Blaese was the last speaker at Symposium '98. He explained a very technical subject in a simple way we could all understand. However, we wondered if we really were understanding? One mother said she looked around the room and saw many of us sitting with our mouths hanging open. Just the idea that there is hope for a cure in the not so distant future was hard to fathom. Previously, cures were only dim hopes - always many years away. Dr. Blaese sounded so certain of this technology.

Dr. Blaese submitted this article on Nov. 19 and plans to keep us updated on developments. We need to keep our hopes from soaring too high just yet. Funding is the major delay in getting testing started. FDA approval is still pending. So parents PRAY; pray for the success of this company and gene repair.


The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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