Researchers, in creating new gene repair molecules, are edging closer to potential applications
Molecular geneticists at Jefferson Medical College are inching closer to using a novel gene repair technique to treat diseases such as cystic fibrosis and sickle cell anemia. While the work remains in the early stages, the scientists are hopeful that their technique will eventually be able to correct the genetic defect responsible for more than 70 percent of cystic fibrosis cases.
Several years ago, Eric Kmiec, Ph.D., associate professor of microbiology and immunology at Thomas Jefferson University in Philadelphia and a member of Jefferson’s Kimmel Cancer Center, developed a technique to repair genes with a single mutation. It involved synthesizing a small molecule termed a chimera, consisting of DNA interspersed with small amounts of RNA, that has the capability to find and attach itself to a certain part of a gene. The small genetic vehicle is designed to trigger the cell’s normal DNA repair system into action as well. The repair mechanism scans the DNA looking for any mismatches or two strands of DNA that don’t seem in sync. When it finds a mismatch, it replaces one of the chemical bases with one that fits better. The scientists, then, can use this natural repair system to correct a bad mutation.
Now, he and his colleagues at the Jefferson Center for Biomedical Research have extended the limits of the current technology. Dr. Kmiec presents his latest research June 13 at the meeting of the American Society of Gene Therapy in Washington, D.C.
Dr. Kmiec’s team was able to correct both point and frameshift genetic mutations – two different types of single gene base mutations – of the § globin gene involved in manufacturing hemoglobin and show the changes were inheritable. He also used the technique to fix copies of the green fluorescent protein gene, which contained one- or two-base deletions. His team has "learned more about how the molecule works," he says, which will "set the stage for direct work in cystic fibrosis and other diseases that are caused by deletions of large parts of DNA." A three-base pair deletion in a gene causes more than 70 percent of cystic fibrosis cases.
Dr. Kmiec had shown previously that the new gene repair technology may hold promise as a treatment for sickle cell anemia and other diseases by correcting the DNA mutation from which they arise.
His aim is to create a "new generation of molecules" to treat disease more effectively. Though the gene correction may occur in only 5 percent of cells, for some diseases, he suggests, this may be enough to help alleviate symptoms, if not cure the disease.
"What’s exciting," he says, "is that we have some newer and better chimera structures that improve gene correction frequency and will move us toward cystic fibrosis and sickle cell anemia applications."
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