Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Abstract

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD. R ecent findings in genetics, stem cell biology, and neural transplantation suggest that brain repair will be possible for the treatment of neurodegenerative diseases (1, 2). Before initiating large clinical trials that test the efficacy of novel donor cells, it is important to determine the clinical feasibility of such cell-based therapies. Transplantation of specific committed neuroblasts (fetal neurons) to the adult human brain provides such a scientific exploration of feasibility of cell-based therapies.The underlying genetic mutation of Huntington's disease (HD) is a polyglutamine repeat in the N-terminal region of the huntingtin gene (3). This mutation results in brain pathology dominated by massive neuronal loss of the medium spiny projection neurons of the caudate and putamen (4). Recent studies of HD postmortem brain tissue show that the N-terminal region of the mutant huntingtin protein aggregates in nuclear inclusions in both cortical and striatal neurons (5-7). These aggregates may represent evidence of ongoing cellular pathology (5-7). Implanted fetal neural cells lacking the mutant HD gene may be able to replace dead or dysfunctional host neurons and reconstitute disrupted neuronal connections (8, 9).Physiological and anatomical evidence in animal st...

Symptomatic Treatment of Huntington Disease

“…The postmortem autopsy of the caudate-putamen demonstrated surviving transplanted cells, with typical morphology, without evidence of immune rejection, and without any evidence of aggregates of huntingtin. 114 Similar pathologic findings were reported after the autopsy of the caudate and putamen of two HD patients who died at 74 and 79 months after the fetal tissue transplantation, confirming the survival of the grafts in the human striatum for more than 6 years, without evidence of graft rejection and without accumulation of ubiquitin-staining inclusions. 115 However, the graft integration in the host striatum was poor, possibly explaining the modest clinical improvement in these patients.…”

Striatal progenitors derived from human ES cells mature into DARPP32 neuronsin vitroand in quinolinic acid-lesioned rats

“…The fact that cells replated in vitro from overgrown grafts differentiated normally into neurons and glia but failed to give rise to MSN, the neurogenesis time schedule of which had passed, is in agreement with this suggestion. It is interesting to mention that human-to-rat xenotransplantation of fetal GE tissue led to overgrowth (30) and that areas containing potentially proliferating cells were observed in grafts analyzed in a patient autopsied 18 months after grafting (25). Apparent overgrowth of human xenograft in rat brain may, therefore, only be a normal consequence of the physiological capacity of proliferation of human neural precursors, essentially revealed because of the size difference between rat and human brain.…”

Cell therapy in Huntington disease

“…83 Notably, grafted fetal striatal cells survive, develop, and integrate into host tissue without being affected by the disease process itself; that is, no mutant huntingtin aggregates were observed within the transplanted region, and the graft showed no signs of immunological rejection. 56 The sparing of grafted tissue from disease progression has also been reported in other transplant cases, including in patients with PD. 86,87,126 The success of allografts of fetal-derived striatal tissue in patients with HD hinges on motor and cognitive improvements following transplantation.…”

“…Although full recovery has not been observed following fetal allografts in the striatum of humans with HD, some suggestions of delayed disease progression indicate positive functional outcomes. 12,13 The contribution of these grafts to functional recovery is enhanced by the fact that implanted cells, lacking the disease-causing gene, do not themselves appear vulnerable to neurodegenerative processes, 56,83 an effect that is also seen in transplants in patients with PD. 86,87,126 All clinical trials to date have been focused on the transplantation of fetal-derived cells into the diseased striatum.…”