Transplantation Of Fetal Neural Tissue Research Articles

Revisiting cell and gene therapies in Huntington's disease.

Neurodegenerative movement disorders, such as Huntington's disease (HD), share a progressive and relentless course with increasing motor disability, linked with neuropsychiatric impairment. These diseases exhibit diverse pathophysiological processes and are a topic of intense experimental and clinical research due to the lack of therapeutic options. Restorative therapies are promising approaches with the potential to restore brain circuits. However, there were less compelling results in the few clinical trials. In this review, we discuss cell replacement therapies applied to animal models and HD patients. We thoroughly describe the initial trials using fetal neural tissue transplantation and recent approaches based on alternative cell sources tested in several animal models. Stem cells were shown to generate the desired neuron phenotype and/or provide growth factors to the degenerating host cells. Besides, genetic approaches such as RNA interference and the CRISPR/Cas9 system have been studied in animal models and human-derived cells. New genetic manipulations have revealed the capability to control or counteract the effect of human gene mutations as described by the use of antisense oligonucleotides in a clinical trial. In HD, innovative strategies are at forefront of human testing and thus other brain genetic diseases may follow similar therapeutic strategies.

Improvement of Spatial Learning and Memory Impairments by Fetal Neural Tissue Transplantation in Experimental Rat Model of Alzheimer’s Disease

ABSTRACT Objective: It is known that the acetylcholinergic afferents of the neocortex from subcortical areas participate in learning and memory. Autopsy studies in cases of Alzheimer’s disease have shown that most of the neurons of nucleus basalis magnocellularis are atrophic or decreased in number. In this study, we searched for whether or not it was possible to improve the impaired learning and memory functions with fetal neural tissue transplantation in an experimental model of Alzheimer ‘s disease. Material & Methods: A total of thirty seven young adult male Wistar albino rats were served as experimental subjects.The nucleus basalis magnocellularis on the right side was destroyed by the injection of kainic acid stereotactically so as to make a model of Alzheimer’s disease. The grafts were obtained from 14-16 day old fetuses of the same genus.After the tissue with cholinergic neurons dissected from ventral forebrain and tissue with non-cholinergic neurons dissected from telencephalic vesicle, cell suspensions were prepared and injected stereotactically to the ipsilateral frontal cortex. Spatial learnig and memory functions were tested by Morris’ water maze tasks. Results: Spatial learning and memory functions in rats were impaired by unilateral lesions of nucleus basalis magnocellularis. The impairment observed during the early period partially improved by the time. It was observed that this amelioration was accelerated with both cholinergic and non-cholinergic fetal neural tissue implantation Conclusion: In our study, improvement of spatial learning and memory impairment with both cholinergic and non-cholinergicfetal neural tissue implantation can be explained by reestablishment of impaired connections via proliferation of limited number of surviving cholinergic neurons creating new synapses, as a result of upregulation of endogenous neural stem cells and activation of trophic mechanisms by implantation, rather than creation of functional synapses between the graft andthe recipient tissue.

Cell therapy for neurological disorders: The elusive goal.

The positive outcomes of the transplantation of fetal neural tissue in adult rat models of a variety of neurological disorders, particularly Parkinson's disease, in the 1970s, and its translation to humans in the 1980s, raised great hopes for patients suffering from these incurable disorders. This resulted in a frantic research globally to find more suitable, reliable, and ethically acceptable alternatives. The discovery of adult stem cells, embryonic stem cells, and more recently, the induced pluripotent cells further raised our expectations. The useful functional recovery in animal models using these cell transplantation techniques coupled with the desperate needs of such patients prompted many surgeons to "jump from the rat-to-man" without scientifically establishing a proof of their utility. Each new development claimed to overcome the limitations, shortcomings, safety, and other technical problems associated with the earlier technique, yet newer difficulties prevented evidence-based acceptance of their clinical use. However, thousands of patients across the globe have received these therapies without a scientifically acceptable proof of their reliability. The present review is an attempt to summarize the current status of cell therapy for neurological disorders.

Metabolism features in the injured hemisphere after experimental traumatic brain injury and transplantation of fetal neural tissue

Metabolism features in the injured hemisphere after experimental traumatic brain injury and transplantation of fetal neural tissue

Effects of tissue neurotransplantation on sceletal muscle tone restoration after experimental mechanical injury of the cerebellum

This work aimed to conduct a comparative study of the restorative effects of transplantation of fetal neural tissue (FNT), olfactory bulb tissue (OBT) and fetal kidney (FK) on the dynamics of muscle hypotonia after cerebellar hemisphere injury in the adult rats. Beam walking test (BWT) allowed detect at least three degrees of hypotonia which correspond to 2, 3, and 4 points. The authors selected animals with function index (FI) by BWT scale strictly lesser than 4 points on the 3rd day after injury. Moderate hypotonia was associated with FI 3 points, severe – 2 points, and mild-4 points. Major differences in the dynamics of the restorative process across study groups were detected at the first month of study: slow recovery of statics and coordination (control); fast recovery (during first 9 days, FK, OBT and FNT groups) that underwent changes by its slow increase during 9th–33rd day. Mild hypotonia in the control group showed itself by the end of the 1st month and on the 9th day in the FK, OBT and FNT groups. Normotony was observed on the 21st (group FNT) and 30th day (groups FK and OBT). These data suggest that neurotransplantation has a significant effect on muscle tone improvement after cerebellar injury, depending on the type of graft.

Impact of Late Transplantation of Fetal Neural Tissue on Hippocampal Cytoarchitectonics in Remote Period after Transient Global Cerebral Ischemia in Rats

Impact of Late Transplantation of Fetal Neural Tissue on Hippocampal Cytoarchitectonics in Remote Period after Transient Global Cerebral Ischemia in Rats

Neural transplantation in Huntington disease: Long-term grafts in two patients

Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. Methods used were pathologic examination, histochemistry, and immunohistochemistry. Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.

Does personality change as a result of fetal tissue transplantation in the brain?

This study examined the effects on personality of transplantation of fetal tissue into the brains of participants in a double-blind placebo control trial for the treatment of Parkinson's disease (PD). Thirty persons with PD (equal numbers of males and females) participated in a larger study investigating the efficacy of transplantation of fetal neural tissue versus placebo surgery. Participants were randomly assigned to receive either the fetal transplant or placebo surgery. The blind was lifted for all patients approximately 13 months after surgery, at which time individuals who had received the placebo surgery could choose to receive the transplant surgery. In this study 12 persons originally received the transplant and 18 received placebo surgery. The NEO Five-Factor Inventory (NEO-FFI), a commonly used measure of personality characteristics, was administered to participants at baseline, 12, and 24 months after surgery. Scores at baseline for the Openness and Agreeableness scales were significantly higher for this sample of PD patients than scores for the normative group. There were no changes on any of the five scales from baseline to 12 months for the total group. The only significant change in the original transplant group was a decrease in Conscientiousness from baseline to 24 months. There were no changes over time among the group who had placebo surgery first and then the transplant. Results indicate that personality, as measured by the NEO-FFI, basically remained stable during the two-year follow-up period of this study. In this case, no change is regarded as a positive outcome.

New Therapeutic Approaches for the Treatment of Huntington’s Disease

The use of transplantation (TR) of fetal neural tissue as a therapeutic method started much later in patients suffering from Huntington's disease (HD) than in those with Parkinson's disease. The clinical trial, following a wide range of animal experiments (neurotoxic models and newly also transgenic mice), includes about 30 HD patients until now. Because of limited use of the human fetal tissue by ethical and technical concerns, there is necessity to search for the alternative sources for neural grafting. The first attempt with xenotransplantation (in 12 HD patients) and with TR of encapsulated genetically modified cells (in 6 HD patients) was performed, but no appreciable improvement of status in any of those patients was noted. Since no effective pharmacological treatment of HD is available, the TR of fetal neural tissue is now the only therapeutic approach which provides a reduction of symptoms in most of grafted patients. The possibilities are enormous offered by neural stem cells, optionally by embryonic stem cells, which could be expanded in cultures, cloned or genetically modified and then grafted into the patient's brain. On the other hand, the neural progenitor and stem cells, normally present within the subependymal layer of the lateral brain ventricles also in adulthood, might be induced to become an endogenous source of glia and neurons participating in the brain's repair.

Fetal hippocampal transplants attenuate CA3 pyramidal cell death resulting from fluid percussion brain injury in the rat.

Transplantation of fetal neural tissue has been demonstrated to prevent neuronal loss in a number of CNS injury models including spinal cord contusion. However, no studies have examined the neuroprotective role of fetal transplants in models of traumatic brain injury. The present study examined the ability of fetal neural grafts to attenuate neuronal loss resulting from lateral fluid percussion (FP) brain injury in the rat. Lateral FP in the rat elicits a focal contusion within the parietal/temporal cortex and induces cell death in a subset of hippocampal CA3 pyramidal neurons. To examine potential neuroprotective effects of fetal neural grafts, either E16 fetal hippocampus, E16 fetal cortex, or sterile lactated Ringers was stereotaxically transplanted directly into contused cortex 2 days after FP brain injury. The effects of fetal transplants upon adjacent injured hippocampal CA3 regions were then assessed at 4 weeks after grafting utilizing quantitative image analysis. Both fetal cortex and hippocampal grafts survived within contused cortex. Fetal hippocampal grafts significantly attenuated CA3 cell death resulting from lateral fluid percussion, while fetal cortical transplants induced a small, but nonsignificant, amelioration of CA3 pyramidal loss. Thus, neuroprotection by fetal grafts appeared to be tissue specific with hippocampal, but not cortical, fetal transplants significantly reducing posttraumatic CA3 loss. In summary, fetal neural transplantation can ameliorate hippocampal cell death following experimental brain injury.

Behavioral effects of neural transplantation.

Considerable evidence suggests that transplantation of fetal neural tissue ameliorates the behavioral deficits observed in a variety of animal models of CNS disorders. However, it is also becoming increasingly clear that neural transplants do not necessarily produce behavioral recovery, and in some cases have either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Regardless, studies demonstrating the successful use of neural transplants in reducing or eliminating behavioral deficits in these animal models has led directly to their clinical application in human neurodegenerative disorders such as Parkinson's disease. This review examines the beneficial and deleterious behavioral consequences of neural transplants in different animal models of human diseases, and discusses the possible mechanisms by which neural transplants might produce behavior recovery.