Background Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson's disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known. Methods We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinson's disease (mean duration, 14 years) to receive a transplant of nerve cells or undergo sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who underwent sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of –3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement. Results The mean (±SD)...

https://www.nejm.org/doi/pdf/10.1056/NEJM200103083441002

Transplantation of embryonic dopamine neurons for severe Parkinson's disease.

Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.

Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease

In the vertebrate central nervous system, multipotential cells have been identified in vitro and in vivo. Defined mitogens cause the proliferation of multipotential cells in vitro, the magnitude of which is sufficient to account for the number of cells in the brain. Factors that control the differentiation of fetal stem cells to neurons and glia have been defined in vitro, and multipotential cells with similar signaling logic can be cultured from the adult central nervous system. Transplanting cells to new sites emphasizes that neuroepithelial cells have the potential to integrate into many brain regions. These results focus attention on how information in external stimuli is translated into the number and types of differentiated cells in the brain. The development of therapies for the reconstruction of the diseased or injured brain will be guided by our understanding of the origin and stability of cell type in the central nervous system.

https://science.sciencemag.org/content/sci/276/5309/66.full.pdf

Stem cells in the central nervous system.

Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication ("off"-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.

A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease†

At no time in the past have the basic and clinical sciences applied to Parkinson's disease been so active. Experimental therapies under study at present promise to improve on the limitations of existing treatments. Future progress in understanding the causation and pathogenesis of the disorder will permit the development of new treatments that will slow, halt, or even reverse the currently inexorable progressive course of Parkinson's disease.

Parkinson's disease. Second of two parts.

Background Trials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinson's disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum. Methods We studied a 59-year-old man with advanced Parkinson's disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 61/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods. Results After transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brai...

https://www.nejm.org/doi/pdf/10.1056/NEJM199504273321702

Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease

Background: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington’s disease (HD). Objective: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. Methods: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. Results: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 ± 6.2 at baseline and 29.7 ± 7.5 12 months after surgery ( p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 ± 6.2 at baseline and 27.5 ± 5.2 at 12 months ( p = 0.03). Conclusions: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.

Bilateral Human Fetal Striatal Transplantation in Huntington's Disease

Infectious issues in human fetal neural transplantation

There is substantial variability worldwide in the donor ages utilized in nigral transplantation programs for the treatment of Parkinson’s disease. In multiple non-human species, it has been repeatedly demonstrated that optimal graft survival occurs when embryonic nigral neurons are harvested before the period of axonal extension, most likely due to axotomy and cell death, of older neurons/1; see 2,3/. Neurons which form the human substantia nigra develop within the ventricular zone primarily between post-ovulatory (PO) day 33 and 63 /2,5/. The nigrostriatal bundle begins to develop at approximately PO day 56/2/. From this data it could be predicted that the optimal period for suspension graft survival would occur before PO day 56 /2,3/. Solid grafts in nonhuman species have been found to have a slightly longer donor age \"window\" for graft harvesting than suspension grafts/see 3/. We compared the ability of solid and suspension grafts of human embryonic dopaminergic neurons at different embryonic ages to survive grafting into 6-OHDA lesioned immunosuppressed rats. Donor age was determined using the atlas of O’Rahilly and Mtiller/4, also see 2/. Suspension grafts survived best from PO day 37 to 56 with diminishing success through PO day 65. These implants displayed numerous healthy tyrosine-hydroxylase-immunoreactive (TH-ir) neurons which sent extensive neuritic processes into the host striatum. Conversely, suspension grafts of human embryonic dopaminergic neurons survived poorly when the donor age was greater than PO 65 days. In contrast to suspension grafts, solid implants of human ventral mesencephalic tissue displayed only modest survival of TH-ir neurons derived from younger donors. These grafts also displayed a limited host innervation. Good/ excellent survival of TH-ir neurons was observed in solid grafts employing embryonic donors between PO day 45 and 65. Only trace numbers of TH-ir neurons Were present within grafts derived from PO 72 tissue. In conclusion, the upper age limit for survival of human embryonic dopaminergic suspension grafts correlates well with the period of development of the human nigrostriatal pathway. Optimal donor ages for human nigral suspension grafts range from PO day 37 to 56 days. The donor age \"window\" for transplantation of solid human embryonic dopaminergic grafts appears to be extended by about nine days in comparison with suspension grafts. In younger age ranges (less than or equal to 41 days), intraparenchymal suspension nigral grafts survive better than solid grafts. The optimal donor age for intraparenchymal solid grafts ranges from PO day 4565. There appears to be a sharp fall-off in the

/pdf/influence-of-donor-age-on-the-survival-of-human-embryonic-4fjasync51.pdf

G. M. Nauert

Papers

Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease

Bilateral Human Fetal Striatal Transplantation in Huntington's Disease

Infectious issues in human fetal neural transplantation

Influence of Donor Age on the Survival of Human Embryonic Dopaminergic Neural Grafts