Setback for Huntington's disease therapy
Brain-tissue transplants don't last very long in patients.
A once-promising clinical therapy for Huntington's disease needs to head back to the lab, research suggests.
Huntington's disease is an inherited, untreatable and fatal disease in which patients develop severe movement and cognitive problems. One approach to treating the disease that picked up steam in the 1990s was the transplantation of healthy neural tissue from the fetuses of women who had undergone elective abortions into the patient's striatum — the brain region most severely affected in the disease. Now the results of the first long-term clinical follow-up of this approach are in1, and they don't bode well.
Neurosurgeon Thomas Freeman of the University of South Florida in Tampa and his colleagues have analysed the brains of three people with Huntington's disease who received fetal striatal-tissue transplants a decade before they died. But instead of slowing or stopping the progress of the disease, the grafts degenerated even more severely than the patients' own tissue.
"Based on our earlier results we were expecting that the grafts would endure," says Freeman. "This tells us we'll have to do a lot of work in the laboratory before going back to the clinic."
Early results for the procedure had seemed promising. Experiments in animal models of the disease, including in rats2 and non-human primates3, demonstrated that transplanted tissue could replace lost striatal neurons and improve behavioural symptoms.
These animal findings, plus positive early clinical results for a similar procedure in Parkinson's disease, motivated Freeman and his colleagues to bring the therapy to people with Huntington's disease. The results were encouraging: patients experienced mild benefits, and autopsies had shown that the grafts had survived and integrated into the brain4,5.
But the benefits of the transplants lasted no more than around two years, and Freeman's new findings show why: the grafts don't last.
"We were surprised to find degeneration that was so severe," says Freeman. "The cells were very unhealthy, and in one patient the grafts were completely gone. All that was left were needle tracts [from the graft injections] and necrotic tissue."
The new findings, published this week in the Proceedings of the National Academy of Sciences, show that 10 years seems to be asking too much of the grafts. Using molecular markers, Freeman's team found evidence of excitotoxicity — a proposed mechanism of cell death in Huntington's disease in which the cells are overactivated — as well as a strong immune response in the grafted regions.
The study offers insights into the mechanism of Huntington's disease. Even though the disease is caused by a mutation in the huntingtin gene, cells with the normal version of the gene still die in the diseased brain — indicating that the striatum does not self-destruct in Huntington's disease, but dies, in part, because of its toxic environment. This mode of death has been observed in animal studies, but this is the first demonstration in humans.
The findings also help to explain why the successful results from early animal studies were so deceptive: at the time, there were no genetic models of the disease. Instead, scientists induced Huntington's disease by chemically destroying the striatum, but leaving the rest of the brain intact. Huntington's disease is now known to cause brain-wide degeneration, even at early stages.
The findings are "evidence that grafting isn't particularly good therapy", says neurologist Roger Albin at the University of Michigan in Ann Arbor. "This limits the likelihood that any kind of engraftment is going to be effective, including stem cells."
But although the transplants "really did not have their hoped-for benefit", they may still have a future, says neurologist Karl Kieburtz at the University of Rochester in New York. "What this tells us is there's a lot of engineering to figure out. The hope was you were bringing something in that could make the whole system stronger. But if you helicopter a bunch of soldiers into a kill zone, they're just as likely to be killed as ground troops."
Freeman, who stopped his clinical trials in 2002 because of the risks associated with the surgery, plans to continue searching for transplant therapies. "It's time to go back to the lab to investigate these new findings," he says. "We have to focus on ways to mitigate the inflammatory response and excitotoxity issues. We're on hold before we sort these things out, and then we'll see."
- Cicchetti, F. et al. Proc. Natl Acad. Sci. USA advance online publication doi:10.1073/pnas.0904239106 (2009).
- Isacson, O. et al. Nature Med. 1, 1189-1194 (1995).
- Kendall, A. L. et al. Nature Med. 4, 727-729 (1998).
- Hauser, R. A. et al. Neurology 58, 687-695 (2002).
- Bachoud-Lévi, A.-C. et al. Lancet Neurol. 5, 303-309 (2006).