ARTICLE IN BRIEF
✓ An autopsy report revealed that while transplanted fetal grafts had become established in two Huntington disease patients, the grafts failed to send out axons to form new connections with adjacent brain tissue, and neither patient had a remission or slowing of symptoms before death.
Autopsies of two Huntington disease (HD) patients who had lived with fetal neural grafts for at least six years provided new insights into transplantation as a potential therapy, but some information was less welcome than desired.
Published in the June 12 Neurology, the autopsy report revealed that while the transplanted grafts had become established in both patients, the grafts failed to send out axons to form new connections with adjacent brain tissue, and neither patient had a remission or slowing of symptoms before death (68:2093–2098).
According to lead author Thomas J. Montine, MD, PhD, the Alvord Endowed Chair in Neuropathology and director of the Division of Neuropathology at the University of Washington School of Medicine in Seattle, some host neurons did infiltrate into the transplanted graft tissue, but only a few. The reasons, he said, remain unclear.
He and co-author C. Dirk Keene, MD, PhD, a neuropathology fellow in the Division of Neuropathology at the school's Harborview Medical Center, discussed the findings and implications for future HD transplants with Neurology Today.
To evaluate graft status, the researchers used pathologic, histochemical, and immunohistochemical tests. Well-demarcated “nests” of fetal grafts within the host neostriatum indicated success of the procedure. Pathologic changes indicative of advanced disease were noted in the neostriatum of both patients. However, few neurofilaments from the grafts crossed into host tissue despite only minimal scarring at the margins of graft and host tissue. In detailed biological studies of the host side of the junctions, more severe gliosis did not seem to explain why the grafts failed to integrate sufficiently for neurofilaments to respond. All but one of 14 grafts survived, with only limited immunosuppression.
“This is the encouraging news,” said Dr. Keene. “The lack of integration however…seems to be more of an obstacle to this therapeutic approach than would have been predicted from animal models and likely was the reason for the limited clinical benefit.”
“The lack of integration doesn't seem to have been caused by scar tissue surrounding the graft and blocking migration,” said Dr. Keene. “There was some gliosis, but the grafts were not walled out.”
Dr. Montine added: “We simply don't know if there is an intrinsic disconnect between graft and host. That is why it is so important to obtain more autopsies in HD patients who have undergone transplants. It's too early to speculate why this is happening. We need to compare what we have found with patients in other trials.”
Similar transplants for Parkinson disease (PD) are further along, but the diseases are different, the researchers added.
“Huntington disease affects the entire brain, as well as other parts of the body. It's a much more difficult problem,” said Dr. Keene. “There are important differences between PD and HD, but the similarity is that transplants are generally placed in the same site in the brain in both disorders.”
AUTOPSY DATA SPARSE
Clinical trials of fetal neural tissue transplants in HD patients have been conducted for nearly a decade. However, until now, there has been no postmortem analysis of graft survival and integration in any long-term survivors, noted Dr. Montine.
Several studies have evaluated the safety and efficacy of transplants, and they too have yielded mixed results. Almost all have relied on shorter-term analysis, he explained. The only other autopsy-based review, in 2000, included a follow-up period of just 18 months (Proc Natl Acad Sci 2000;97:13877–13882).
Thomas B. Freeman, MD, professor of neurosurgery and medical director of the Center of Excellence for Aging and Brain Repair at the University of South Florida in Tampa, led that study. He told Neurology Today that despite the failure of the transplanted cells to integrate and the lack of clinical improvement, the study provides important information.
Dr. Freeman said the study confirms survival of the grafts even longer than previously demonstrated without immunosuppression, even though they do not make connections to the host with longer survival. “It also supports preliminary evidence that surviving grafts do not increase survival for patients with current transplant techniques,” he said.
The current histological findings are nearly identical to those he and his colleagues reported in the 2000 study, he said in an e-mail. “The point that they did not include — and which we have discussed in many of our review articles — is this: Without connection between graft and host, there is little chance for the graft to provide the trophic support to prevent the widespread degeneration in the entire brain in HD.”
In addition, the projections of striatal neurons are only part of the disease, he stressed. “We did not see more than one or two neurons extending from the transplant to normal targets. However, we did see connectivity between the host brain and the graft, connecting dopaminergic neurons from the substantia nigra to the striatum and the graft. Retrograde trophic support of this region may be possible, but there is no evidence to support this in animals or humans.”
According to Dr. Freeman, even if better transplant techniques can be developed to facilitate integration, it is unlikely that recipients will experience much improvement.
“We believe that HD transplants at best set the disease process back only two years, with more adverse events than in PD transplants,” he said. “This is why we recommended stopping trials in any but early stage HD patients without brain atrophy, which seems to have been responsible for the adverse events we encountered.”
A MATTER OF TIME?
Without cell integration, fetal graft transplants remain of questionable efficacy in HD, noted Samuel Frank, MD, assistant professor of neurology at Boston University, and Kevin Biglan, MD, assistant professor of neurology at the University of Rochester Medical Center in New York, in an accompanying editorial in the June 12 Neurology (68:2055–2056).
“Ongoing research needs to demonstrate the possibility of transplant cell integration as well as determine the optimal cell type,” they commented.
“Pathologic studies of fetal cell transplantation in PD have demonstrated that cells integrate into the basal ganglia and produce dopamine in the intended areas. Why would cells integrate well and become functional in the brains of patients with PD but not HD? Clearly, this discrepancy highlights that the cell type and location are important, but circumstances beyond the right cell in the right place are necessary…we know too little how to ensure integration. In addition, HD affects the entire brain, and structures beyond the striatum may need to be involved in therapy for successful treatment of HD.”
They said conclusions from the study must be made with caution. “The use of gene transfer technologies and infusion of trophic factors and various delivery systems to the brain (such as gelatinous carriers) may be needed in combination with cell transplantation. However, prior to initiating even small trials in humans, we should understand the safety of specific procedures better and determine what is necessary for differentiation and integration.”
Dr. Montine said the research problems were not insurmountable, and that more time is needed to consider the potential value of the approach.
“Clinical trials answer a specific question,” he said. “It was a surprise to me that there was no integration given the amount of data we have from animal studies. We need a clinical trial to work out that question.”
He also noted that to date, the only autopsies have been on patients who received grafts “in the early days” of HD transplants and that newer techniques have been and are currently being developed and tested.
“These are technical issues that need to be worked out. It could have been worse — the grafts could have integrated fully without any improvement in patients. Our study is mixed. There is bad news, but it isn't damning news.”