Sickle cell anemia, which in 1949 became the first illness described as a molecular disease, might soon become one of the first diseases to be treated successfully with gene therapy.
The latest advancement marks progress for both gene therapy and sickle cell anemia treatment. Researchers injected a gene into mice that stopped red blood cells from changing into the "sickle" shape characteristic of the disease.
The treatment, detailed in Thursday's issue of the journal Science, looks promising, researchers said, but some safety issues loom. The biggest concern is that an altered human immunodeficiency virus (HIV) carries the corrective gene into the cells.
"It doesn't cause AIDS, but there is a danger it could recombine and change into an AIDS-causing virus," said Dr. Josef Prchal, co-director of the Comprehensive Sickle Cell Center at Baylor College of Medicine, who evaluated the study.
Sickle cell anemia is a genetic blood disorder that causes normally round and pliable red blood cells to become pointy and hard, blocking capillaries and causing myriad complications including anemia, stroke, recurring bouts of severe pain and organ damage.
The disease is most prominent in African Americans, affecting one in 400. It affects about one in 1,000 to 1,400 Hispanics.
The life expectancy of people with sickle cell is about 43 years. That's better than 20 years ago when it was only about 19. But the improvement is due to better treatments for infection as opposed for treatments for sickle cell per se.
Despite safety concerns, Prchal remained optimistic about the gene therapy's potential.
"It's a remarkable improvement and offers hope that sickle cell disease could be cured in humans," Prchal said. "This is fantastic because this is the first time it's very realistic to cure the disease."
The researchers, from the Massachusetts Institute of Technology, the Albert Einstein College of Medicine, the Hospital for Sick Children in Toronto and others, hope to perform non-human primate studies next year. Depending on the results, human trials could soon follow.
The researchers used two mouse models genetically engineered to carry the human sickle cell anemia gene.
They removed bone marrow from the mice, and "ablated" it -- they removed all traces of disease. In a dish, they treated the bone marrow with the anti-sickling gene therapy.
Hemoglobin is the substance in blood that produces red blood cells. Scientists have found that newborn and fetal hemoglobin blocks sickling, so the researchers modeled their therapeutic gene after that.
The mice were free of sickle cell disease for 10 weeks after the bone marrow was re-injected. Researchers continue to monitor them, and will use them to model future studies.
Scientists have been trying to get a sickle-blocking gene into diseased cells for about a decade, but have found it difficult to get the gene to "transfect," or become a part of the genome of the animal being tested.
The altered HIV virus that the researchers used, called lantivirus, was able to work the gene into the genome of the mice.
In doing that, however, there is a danger that the new genetic sequence will combine with the DNA already present to form new genes that could result in new diseases, like an unknown strain of HIV.
Or, the DNA could recombine and activate tumor-forming genes. Whatever change occurs, it will likely be permanent.
"Whatever the virus does, it can't be undone once the transformed cells are put back into the patient," said Eric Wickstrom, a professor of microbiology and immunology at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.
But the researchers emphasized such problems are unlikely.
"There's a very small possibility of that occurring and it hasn’t been demonstrated to date," said Robert Pawliuk, a researcher at the Harvard MIT division of health sciences and Genetix Pharmaceuticals, and an author of the study.
The head researcher on the study, Dr. Philippe Leboulch, is chief scientific officer of Genetix Pharmaceuticals.
The lantivirus appears to be the most powerful vehicle researchers have found to date for incorporating genes into a genome.
Another obstacle to be overcome is the method of ablating the bone marrow. The procedure is too toxic for humans now. But researchers in various labs are making progress towards milder methods of cleaning bone marrow that humans could tolerate.
