Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

Abstract

Huntington disease is a neurological movement disorder involving massive neuronal death in the caudate-putamen region of the brain. Neither preventive nor curative therapy exists for this disease. The implantation of cross-species striatal neural precursor cells into the lesioned striatum of nonhuman primates (baboons) reduced the abnormal movements seen in the disease model. These abnormal movements reappeared after immunological rejection of the implanted striatal cells and were not modified by transplantation with nonstriatal cells. These findings encourage further experimentation toward the use of cell sources other than human fetal cells in a potential clinical application to Huntington disease.Huntington disease (HD) evolves over several years with a continuous deterioration of the patient's condition. The motor and cognitive symptoms are associated with neuronal loss in the caudate-putamen, cerebral cortex, globus pallidus, and substantia nigra (1-5). The neuropathological changes in HD are dominated by the severe atrophy, neuronal cell loss, and astrocytic reaction in the caudate-putamen complex (striatum). By intrastriatal application of the neurotoxin ibotenic acid (IA), we have created a striatal pathology similar to HD in the baboon to evaluate therapeutic strategies, such as neuronal implantation (6). Intrastriatal injections of the glutamate receptor agonist IA and other glutamate agonists cause severe neuronal loss of striatal output neurons but spare axons of passage and striatal afferents, a characteristic pathological feature of HD (6-10). The many neuropathological and neurochemical similarities between such striatal lesions in the rat brain and alterations found in the brain of choreic patients have suggested a role for glutamate receptor agonists in the neurodegenerative mechanisms underlying HD (8,(10)(11)(12). Previous studies have utilized intrastriatal injections of IA, quinolinic, or kainic acid to produce a primate model of HD (6,13,14). Whatever the toxin used, the primates receiving such striatal lesions all display a variety of abnormal movements similar to the symptoms observed in HD patients, including dyskinesia, orofacial dyskinesia, chorea, and dystonia. These findings contrast sharply with previous rat models where involuntary choreiform movements have not been described (15)(16)(17)(18)(19)(20). We therefore used a primate model of HD to evaluate whether striatal cell replacement in the degenerated striatum could ameliorate the characteristic motor symptoms observed. We also investigated whether such symptoms would reappear after removal of immunosuppressive treatment and if implanted nonstriatal neural precursor cells could have a beneficial effect. MATERIALS AND METHODSWe performed intrastriatal stereotaxic injections of IA into the right caudate-putamen complex of 15 baboons. Six weeks later, 5 of these animals received fetal rat striatal cells by injection into the lesioned caudate-putamen. In addition to these 5 transplanted animals a 6th baboon received a contro...

Intravenous administration of human neural stem cells induces functional recovery in Huntington's disease rat model

“…The transplantation of neural tissue has been shown to improve functional outcome (Hantraye et al, 1992;Hurelbrink et al, 2000), to restore electrophysiological sensitivity to dopamine , neuronal differentiation, and fiber outgrowth from grafts in an animal model of HD .…”

Cell therapy in Huntington disease

“…[41][42][43][44] In primates, striatal allografts and xenografts survive, differentiate into mature DARPP-32-positive striatal cells, and receive dopaminergic innervation. 70,84,115 These changes are correlated with improvements in both motor performance, 70,84 including recovery in a test of skilled motor performance, 84 and cognitive function. 115 Cellular and behavioral improvements following fetal-derived striatal cell transplantation are thought to occur through circuit reconstruction, the normalization of neurotransmitter release, and/or the production of trophic factors.…”

“…All striatal cell types from the allo-and xenotransplantation of fetal-or embryonic-derived striatal tissue have been shown to survive, grow, and establish functional afferent and efferent connections to host tissue 25,98,101,126 and display appropriate electrophysiological properties 25,29,113 in both rodent 25,45,77,113 and primate models 70,84 of HD. Although the authors of 1 study have reported no clinically relevant behavioral improvements following striatal grafting in a transgenic mouse model of HD, 45 others have demonstrated that behavioral motor deficits 18,54 are improved by the transplantation of striatal tissue into the degenerate striatum of rodents 113 and primates.…”

“…Although the authors of 1 study have reported no clinically relevant behavioral improvements following striatal grafting in a transgenic mouse model of HD, 45 others have demonstrated that behavioral motor deficits 18,54 are improved by the transplantation of striatal tissue into the degenerate striatum of rodents 113 and primates. 70,84 Both pre-and postoperative motor training in animal models of HD have also had a significant impact on functional recovery, presumably by enhancing the plasticity of grafts and host circuitry. [41][42][43][44] In primates, striatal allografts and xenografts survive, differentiate into mature DARPP-32-positive striatal cells, and receive dopaminergic innervation.…”

Neurodegeneration and Ageing: A Fatal Encounter

“…Extensive work has been performed on transplanting foetal-derived cells into the brain of HD patients. Several clinical trials performed on mice and humans diseased brain suggest that transplanted foetal striatal allografts can well survive and establish functional connections to host tissues, but this can only delay the disease progression and does not drive a complete rescue [92][93][94][95][96]. Stem cells transplantation appears to have more therapeutic potential than fetal-derived cells because of the minimal chances of host rejection.…”