RESUMO
Individuals with Parkinson's disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson's disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.
Assuntos
Mesencéfalo , Células-Tronco Neurais , Doença de Parkinson , Putamen , Adolescente , Adulto , Idoso , Aloenxertos , Dopamina/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Mesencéfalo/cirurgia , Pessoa de Meia-Idade , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Células-Tronco Neurais/transplante , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/cirurgia , Putamen/metabolismo , Putamen/patologia , Putamen/cirurgiaRESUMO
Fetal brain grafting has been used successfully in the restoration of striatal function in rat and non human primate models of Huntington's disease (HD). This is a report of the first clinical trial of this procedure applied to a 37 year old Mexican female with moderate to severe HD of 9 years evolution. The two striata from a 13 week-old human fetus were homotopically transplanted to 4 cavities in the ventricular wall of the right caudate nucleus. The months after surgery, her neurologic and neuropsychologic evaluations revealed the stabilization of many of her signs and most neuropsychologic parameters, a moderate improvement of her choreic movements, predominantly in the face, of her ability to define and express ideas in oral and written form, and of her articulatory agility, as well as of some activities of her daily life and social behavior. There was a slight deterioration of her gait and posture. Her saccadic system and optokinetic nystagmus, and her visuospatial and visuoperceptual functions were deteriorated.
Assuntos
Transplante de Tecido Encefálico , Corpo Estriado/transplante , Transplante de Tecido Fetal , Doença de Huntington/cirurgia , Adulto , Feminino , Seguimentos , Humanos , Doença de Huntington/fisiopatologia , Exame Neurológico , Gravidez , Testes PsicológicosRESUMO
We report on the clinical status of 5 patients with Parkinson's disease (PD) 3 years after autologous adrenal medullary (AM)-to-caudate nucleus (CN) implantation, and of 2 PD patients, 2 years after fetal ventral mesencephalon (VM)- and fetal adrenal (A)-to-CN homotransplantation. Current clinical evaluation of 4 of the AM grafted patients revealed sustained bilateral amelioration of their PD signs, most notably of rigidity, postural imbalance and gait disturbances, resulting in a substantial improvement in their quality of life. The disease-related dystonia of one of them disappeared only 2 years after surgery. The levodopa requirements of 2 of these patients and the anticholinergic therapy of another have been reduced. In agreement with the satisfactory clinical evaluation of these 4 patients, their neuropsychological and electrophysiological improvements, initially registered 3 months after surgery, have been maintained for 3 years. After 1 year of significant recovery, the 5th patient of this group has almost returned to her preoperative state. The 2 homotransplanted patients also showed sustained bilateral improvement of their PD signs. Two years after surgery, the most improved signs of the fetal VM case were rigidity, bradykinesia, postural imbalance, gait disturbances and facial expression. The fetal A case has only shown amelioration of rigidity and bradykinesia. Neither of them has shown significant neuropsychological changes. Their current levodopa requirements are less than before surgery. The improvements shown here by PD patients after brain tissue grafts go beyond those obtained using any other therapeutic approach, when levodopa fails. Although more studies and the development of these procedures are obviously required, these initial human trials appear to be resisting the test of time.
Assuntos
Glândulas Suprarrenais/transplante , Medula Suprarrenal/transplante , Transplante de Tecido Encefálico , Núcleo Caudado , Transplante de Tecido Fetal , Mesencéfalo/transplante , Doença de Parkinson/cirurgia , Glândulas Suprarrenais/embriologia , Adulto , Terapia Combinada , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Humanos , Levodopa/administração & dosagem , Levodopa/uso terapêutico , Masculino , Mesencéfalo/embriologia , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Índice de Gravidade de Doença , Transplante AutólogoRESUMO
Four cases of transplant to the brain (striatum) of the ventral mesencephalic area (VMA) and three adrenal glands (A) to patients with Parkinson's disease are described as a new alternative for the improvement of this disease. The patients who received VMA showed a very significant improvement in the rigidity, bradykinesia, alterations in walking and posture, as well as the facial expression. Three of the four patients have returned to work. The group that received A tissue, showed a discreet improvement in the rigidity and bradykinesia, but none in the other signs of the disease. These patients are able to accomplish their daily needs, but two are unable to return to work. The differences which we observed between patients receiving VMA and A transplants, might be related to the heterogeneity of the disease, although we believe that the type of graft was responsible of these differences. Our results with the use of VMA, as well as that of other groups, are encouraging, although it is important to clearly establish that it is a procedure which is still in an experimental phase, requiring caution, and should only be practiced in highly qualified centers of clinical research.