Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration

Abstract

The clinical evaluation of neural transplantation as a potential treatment for Huntington's disease (HD) was initiated in an attempt to replace lost neurons and improve patient outcomes. Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits. Their brains were evaluated immunohistochemically and with electron microscopy for markers of projection neurons and interneurons, inflammatory cells, abnormal huntingtin protein, and host-derived connectivity. Surviving grafts were identified bilaterally in 2 of the subjects and displayed classic striatal projection neurons and interneurons. Genetic markers of HD were not expressed within the graft. Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient's neurons, particularly the projection neuron subtype; (iv) graft survival is attenuated in the caudate in comparison to the putamen in HD; (v) glutamatergic cortical neurons project to transplanted striatal neurons; and (vi) microglial inflammatory changes in the grafts specifically target the neuronal components of the grafts. These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms. excitotoxicity ͉ inflammation ͉ mutant huntingtin ͉ glutamate ͉ microglia

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…Yet medial ganglionic eminence components are also important for both the proper development of striatal structures, and for their functional integration [25]. This may explain, at least in part, the lack of functional integration in the clinical trial reported by Hauser et al [13], in which the grafts only consisted of the most lateral part of the lateral ganglionic eminence [13,26].…”

Human Pluripotent Stem Cell Therapy for Huntington's Disease: Technical, Immunological, and Safety Challenges

“…However, an immune reaction has been observed at least in some cases. Recent studies have shown either the presence of anti-HLAs or inflammation [22,[105][106][107]. Krystkowiak et al [107] reported that as many as half of the HD patients had immunization develop against donor antigens during their phase II multi-center study of fetal neural transplants, with 1 patient showing full clinical, radiological, and biological symptoms of immune rejection.…”

“…This function is highly dependent on the integrity of striatal neural networks, in particular the fronto-striatal circuitry [19,20]. In the few transplanted patients autopsied, histological analyses at 18 months [21] to 10 years [9,22] after transplantation have provided both qualitative and quantitative measurement of cellular biology outcome of therapeutic fetal grafts. Human fetal grafts in these patients are rather small, representing no more than~4% of the corpus striatum volume and contain less than 60% of P-zones (i.e., region selectively positive for striatal interneurons or for striatal projection neurons markers [22].…”

“…The main challenge for quality control (QC) of fetal grafts is the accuracy of the dissection (in HD clinical trials), either of the whole ganglionic eminences, the LGE, or the far lateral ganglionic eminences, the most lateral half of the LGE. In each cases, the primary focus is on the harvest of tissue that would yield the most DARPP32+ neurons and striatal like tissue (P-zone, i.e., the LGE/far lateral ganglionic eminences) [7,16,22,[74][75][76]. In addition, a secondary focus is on the complementary harvest of tissue to enhance the survival of LGE-derived MSNs or on the restoration of all striatal cell type, as with the harvest of whole GE [6,8,77].…”

“…In the few transplanted patients autopsied, histological analyses at 18 months [21] to 10 years [9,22] after transplantation have provided both qualitative and quantitative measurement of cellular biology outcome of therapeutic fetal grafts. Human fetal grafts in these patients are rather small, representing no more than~4% of the corpus striatum volume and contain less than 60% of P-zones (i.e., region selectively positive for striatal interneurons or for striatal projection neurons markers [22]. These graft-derived Pzones are specifically surrounded by activated microglia, whereas MSNs inside these regions are found more markedly positive for apoptotic markers.…”