Researchers have used a kind of "molecular scissors" to snip out a defective stretch of genetic material from the precursors of sickle cells and replace it with a new one. The laboratory success, reported in tomorrow's Science, could eventually offer a remedy for sickle cell anemia.
People with sickle cell anemia have a single base pair anomaly in the gene that codes for a protein in hemoglobin, the oxygen-carrying molecule in red blood cells. Efforts to introduce normal copies of the gene have been slowed by the considerable challenge of regulating the gene's activity. To sidestep this problem, geneticist Bruce Sullenger and his colleagues at Duke University Medical Center in Durham, North Carolina, didn't try to fix the gene itself. Instead, they corrected the messenger RNA--the molecule that helps translate DNA into protein--made from the gene.
The team engineered ribozymes, enzymes that typically "edit" nonsense sequences from RNA, to recognize a site on the mRNA that is translated into the faulty protein, called sickle -globin. To these ribozymes the group attached mRNA that encodes -globin, a component of fetal hemoglobin (and some adult hemoglobin) that appears to hamper sickling. When added to red blood cell precursors taken from sickle cell patients, the ribozymes cut out the faulty stretch of mRNA and pasted in the globin code. The researchers say that a technique such as this one--which would repair just 10% of a person's RNA--could nevertheless make a sizable difference to sickle cell sufferers, since patients with even a slightly higher proportion of>-globin have less severe symptoms.
The team's RNA repair is "an elegant strategy," says Michel Sadelain, a geneticist at Memorial Sloan-Kettering Cancer Center in New York City. "You let the cell regulate expression of the its own globin, which is a very interesting and exciting prospect." But other substantial hurdles remain, such as efficiently delivering the ribozymes to fledgling blood cells and keeping them working. Meanwhile, the Duke team hopes to test their ribozymes in humans in 2 to 3 years.