Dec. 29, 1999 The technique may someday be used in treating inherited disease
Researchers at Jefferson Medical College have used an innovative “gene repair” technique to genetically change white albino mice hairs to black. The technique has not only turned hairs black, but has showed that such changes are stable and long lasting in skin cells.
The work holds promise as a potential treatment for some hereditary diseases by correcting the genetic mutation from which they arise.
Kyonggeun Yoon, PhD, associate professor of dermatology and cutaneous biology and biochemistry and molecular pharmacology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and postdoctoral fellow Vitali Alexeev, PhD, in collaboration with a team of scientists at the University of Pennsylvania, corrected a single alteration in the gene that controls skin color in albino mice cells.
The scientists, in what they dub “localized gene therapy,” delivered a small oligonucleotide – DNA interspersed with small amounts of RNA – to the melanocytes, or skin color-producing cells. The “oligo” triggers the actual gene repair process. They both injected the oligonucleotide and applied it topically.
The researchers’ work appears in the January issue of the journal Nature Biotechnology.
“We showed that it’s possible to change the hair color in a live animal, and not just in the color-producing cells cultured in a test tube,” says Dr. Alexeev, noting that only a few tiny hairs were blackened and were not visible without a microscope. Last year, Dr. Yoon and Dr. Alexeev reported that, using this gene repair technique, they could change mouse melanocytes from white to black in the test tube.
The scientists would like to continue to refine their technique. “We have a lot to improve on, such as oligonucleotide delivery to the melanocytes,” says Dr. Yoon, who is also a member of the Jefferson Institute of Molecular Medicine. “We’re still trying to find the optimum conditions for delivery of the oligonucleotides into mouse skin. The skin is a good organ to do this. It’s accessible and easy to monitor for changes.”
The researchers also hope to improve the delivery system because mouse and human skin differ.
In the gene repair technique, the gene alteration, known as a “point mutation,” was in the gene for a key enzyme, tyrosinase, which is involved in making melanin and in pigmentation. By correcting the alteration, tyrosinase activity was restored and melanin was again produced.
Dr. Yoon used the technique on melanin-producing cells as a model system to test a hypothesis. “We wanted to see what we could visualize and follow using this system,” she says.
Dr. Yoon and former Jefferson researcher Eric Kmiec, Ph.D., developed the gene-fixing technique several years ago. Scientists can synthesize a small oligonucleotide 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.
The gene-repair technique is far from perfected, Dr. Yoon says. “Much more research is needed to improve the design and make this technology generally applicable.”
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