Huntington disease is one of the most challenging diseases for neurologists; for a patient who has the gene, disease progression is foreordained, relentless, and entirely untreatable. Progress in understanding disease pathogenesis may eventually lead to rational pharmacotherapy, but until then, fetal transplant surgery has been seen as perhaps the best hope for treatment. In this context, a new study offers sobering news. While transplants to the striatum can survive and integrate into host tissue, the surgery carries a high risk of complications, and may not significantly alter the course of the disease.
The study was led by Robert Hauser, MD, Associate Professor of Neurology, Pharmacology and Experimental Therapeutics and Director of the University of South Florida Movement Disorders Center in Tampa.
As detailed in the March 12th issue of Neurology, Dr. Hauser and colleagues enrolled seven genetically confirmed Huntington disease (HD) patients who had been symptomatic for four to 12 years. Patients underwent a year of pre-implantation clinical evaluation to establish a baseline rate of motor function decline, which they measured with the motor portion of the United Huntington's Disease Rating Scale (UHDRS).
Patients received two to eight fetal striata, implanted bilaterally in two staged procedures one to 14 weeks apart. The implants were targeted to the postcomissural putamen, the motor area of the striatum, with other areas targeted as well if sufficient tissue was available. Cyclosporine immunosuppression was given for six months after surgery. Patients also underwent PET scanning before and at six-month intervals after implantation.
The study was designed only to test the safety and feasibility of implantation, but, Dr. Hauser said in a phone interview, “We hoped it might be able to slow progression, based on being able to replace some of the cells that degenerate.” In that regard, the results were equivocal. The mean UHDRS motor score was 32.9 at baseline, and 29.7 at 12 months post-surgery (on this scale, a decline in score represents an improvement in function). The p value for this difference was 0.24, indicating no significant difference.
For a progressive disease such as HD, this may be good news, if it really represents halting or slowing deterioration in motor function. However, several factors prevent a firm conclusion in this regard.
In his discussion in the article, Dr. Hauser noted the possibility of a significant and prolonged placebo effect, as was seen in the double-blind study of porcine transplants in Parkinson disease. In addition, the possibility of investigator bias cannot be ruled out in any open study.
NO CAUSE FOR OPTIMISM
A further caution against any optimistic interpretation of the results was raised in an accompanying editorial by Timothy Greenamyre, MD, PhD, Program Director of Research in the Neuromuscular Division of Emory University School of Medicine, and Ira Shoulson, MD, PhD, Professor of Neurology, Pharmacology & Medicine at of the University of Rochester School of Medicine and Dentistry.
“Given the size of the confidence intervals for the changes from baseline to 12 months,” they wrote, “[the investigators] have not demonstrated a lack of significant worsening.”
On the other hand, evidence did point toward survival and integration of the grafted tissue. PET imaging showed maintenance of metabolic activity in the lentiform nucleus and preservation of D1 dopamine receptor binding in the putamen.
Figure. Dr. Timothy ...Image Tools
According to Dr. Hauser, this “may suggest survival of region-appropriate transplanted neurons, but this remains to be proven.” Supporting evidence came from one patient who died of cardiac arrhythmia 18 months after implantation. Histological evaluation indicated that the grafts had begun to integrate into the host tissue, with host dopaminergic fibers extending into the graft and no evidence of immune rejection.
These results, however, were accompanied by significant and potentially serious adverse events. Three patients experienced subdural hemorrhages. One patient was asymptomatic, and another developed confusion for several weeks and then improved. The third patient, who developed bilateral subdural hemorrhages (SDH) after falling and hitting her head, had motor and cognitive worsening that only partially improved following drainage. This patient also had the worst overall clinical outcome, which Dr. Hauser suggested may have been more related to the effects of the hemorrhages than to the transplantation.
Dr. Hauser speculated that the high rate of hemorrhage might have been related to the cortical atrophy, which accompanies disease progression. Should future transplant trials occur, Dr. Hauser said, “there's reason to hope we could reduce the risk of SDH by going to patients with less atrophy,” namely those earlier in the disease course.
DEBATE ON MORE TRANSPLANT TRIALS
Whether further transplant trials should proceed, however, is an open question. In an interview, Dr. Greenamyre expressed skepticism that transplants would ever provide meaningful treatment of HD. Unlike the situation in Parkinson disease, in which the motor symptoms are caused primarily by loss of a small and specific set of dopamine neurons, much more of the brain is involved in HD, including the striatum, globus pallidus, cortex, hippocampus and hypothalamus, as well as other regions.
“Although the striatum is affected most severely,” Dr. Greenamyre said, “if we replace only eight to ten percent of the striatum, which in turn represents only 20 percent of the degeneration in HD, are we likely to have a major impact? Probably not.” Even if there were benefits, he asked, “how long could they last as the surrounding and connecting neurons continue to die?”
Paul Greene, MD, Associate Professor of Clinical Neurology at Columbia University College of Physicians and Surgeons, who was one of the investigators in the double-blind trial of fetal transplants in Parkinson disease, is more sanguine about the potential benefits of transplants in HD.
“The issue is going to turn on the cortical pathology,” he suggested in a phone interview. Whatever the potential for motor benefit, he said, the real devastating debility in HD is cognitive. If this degeneration is secondary to striatal loss, then transplants may have an important role independent of their motor effects. If the degeneration in the cortex is primary, however, he thinks transplants would then be “doomed to have a relatively small role in treatment.” Further understanding of the pathogenesis in animal models may resolve that question.
NEED FOR DOUBLE-BLINDED TRIALS
In the meantime, should more transplant trials proceed? Dr. Greenamyre is skeptical. “Families affected by Huntington disease, and those of us who help to care for them, are desperate for a cure,” he said, “or at least better treatment options. As such, there is a tendency to grasp at straws. Given the current state of the art of fetal transplantation in Huntington disease, however, I could not in good conscience recommend it to even the most desperate affected individual.”
If there are future trials, both Dr. Hauser and Dr. Greenamyre feel strongly they should be double-blinded. “The problem with further open label trials,” said Dr. Hauser, “is that we can't get rid of the placebo effect, and we wouldn't know what efficacy we were or were not seeing.”
Dr. Hauser suggested that before any future trial proceed, there needs to be “careful consideration whether there is sufficient promise, and whether we could sufficiently reduce the risk” of the procedure.
While doubtful of the wisdom of any future trial, Dr. Greenamyre doesn't rule them out entirely. He noted that other open studies have had less severe complications, and he speculated that results from those studies might support a small blinded and controlled pilot study.
Despite hoping for answers from animal models, Dr. Greene said that double-blind human trials may be the only option for determining if the transplants can succeed in humans. “We often get misled by animal models,” Dr. Greene noted. The only way to really feel confident the procedure will, or will not, work in people, he thinks, may be to do the trial. “I'm not optimistic,” he said, “but I think it is something that has to be tried.”