CHAPEL HILL -- In experiments that hold strong promise for victims of thalassemia, a genetic illness of the blood afflicting people of the Mediterranean, Middle East and Southeast Asia, scientists have succeeded in restoring production of hemoglobin, the molecule in blood that carries oxygen to tissues.
Those born with thalassemia cannot make enough hemoglobin on their own.
"This work is important because it uses a novel approach to treat a genetic problem," said Dr. Ryszard Kole, professor of pharmacology at the University of North Carolina at Chapel Hill School of Medicine. "Instead of replacing a defective gene, we have repaired the RNA that was produced from it. We have not used this method in patients yet, but in their blood cells in the laboratory. We hope that in the future we'll be able to treat thalassemia more successfully than today."
A report on the research appears in the Aug. 15 issue of the Proceedings of the National Academy of Sciences. Besides Kole, authors include Drs. Halina Sierakowska of UNC-CH, Giuseppina Lacerra and Clementina Carestia of Naples, Italy, Suthat Foucharoen of Bangkok, Thailand, James Summerton of Gene Tools in Corvallis, Ore., and Dwight Weller of AVI Biopharma in Portland, Ore.
Thalassemia is one of the most common genetic diseases in humans, the authors wrote. "Approximately 80 million people are carriers of the thalassemia trait, and the percentage of carriers worldwide is increasing. ... Increases in the number of patients, presently several hundred thousand, are held down by high infant mortality in underdeveloped countries, by population screening, genetic counseling and abortion."
Victims often suffer severe anemia, bone defects and heart, liver and spleen dysfunction, Kole said. Mutations in the genetic machinery that produces hemoglobin cause the illness.
In laboratory experiments, researchers used what are called antisense oligonucleotides, which are like mirror images of defective parts of genes responsible for producing hemoglobin, to block those defective parts specifically. The antisense oligonucleotides restored correct production of beta-globin, a sub-unit of hemoglobin, and enabled the cells to make far more hemoglobin than they had previously.
"Basically we forced the cell's internal machinery to restore correct splicing of RNA that was made from the defective beta-globulin gene," Cole said. "RNA splicing is a process that is required to make the RNA functional, so that the beta-globulin protein can be made on it.
"In the cases of thalassemia we studied, RNA splicing was damaged by the genetic mutations that caused the disease," the scientist said. "By repairing splicing, we were able to get affected cells to produce about 50 percent of the hemoglobin than normal cells do. That is a major improvement."
Indications are that while the correction would not be permanent, it could last for months, he said. Advantages are that the possible therapy would be simpler than gene therapy and could be stopped more easily than gene therapy if negative side effects occurred.
"We are several steps away from being able to use this novel approach in humans but we have demonstrated that it is quite promising as a potential new treatment," Kole said. "Modification of splicing by antisense oligonucleotides also should be applicable to other genetic disorders and to certain cancers."
The UNC-CH team already has begun extending its work to mice with thalassemia, he said. The National Heart, Lung and Blood Institute and Italy's National Research Council supported the experiments.
Note: Kole can be reached at (919) 966-1143 or mailto:kole@med.unc.edu.