Cellular replacement therapy for Parkinson's disease--where we are today?
The concept of replacing lost dopamine neurons in Parkinson's disease using mesencephalic brain cells from fetal cadavers has been supported by over 20 years of research in animals and over a decade of clinical studies. The ambitious goal of these studies was no less than a molecular and cellular "cure" for Parkinson's disease, other neurodegenerative diseases, and spinal cord injury. Much research has been done in rodents, and a few studies have been done in nonhuman primate models. Early uncontrolled clinical reports were enthusiastic, but the outcome of the first randomized, double blind, controlled study challenged the idea that dopamine replacement cells can cure Parkinson's disease, although there were some significant positive findings. Were the earlier animal studies and clinical reports wrong? Should we give up on the goal? Some aspects of the trial design and implantation methods may have led to lack of effects and to some side effects such as dyskinesias. But a detailed review of clinical neural transplants published to date still suggests that neural transplantation variably reverses some aspects of Parkinson's disease, although differing methods make exact comparisons difficult. While the randomized clinical studies have been in progress, new methods have shown promise for increasing transplant survival and distribution, reconstructing the circuits to provide dopamine to the appropriate targets and with normal regulation. Selected promising new strategies are reviewed that block apoptosis induced by tissue dissection, promote vascularization of grafts, reduce oxidant stress, provide key growth factors, and counteract adverse effects of increased age. New sources of replacement cells and stem cells may provide additional advantages for the future. Full recovery from parkinsonism appears not only to be possible, but a reliable cell replacement treatment may finally be near.
Redmond
D Eugene
DE
Department of Psychiatry, Yale University School of Medicine, USA. eugene.redmond@yale.edu
D000818:Animals; D017209:Apoptosis; D016380:Brain Tissue Transplantation / Q000009:adverse effects / Q000379:methods / Q000639:trends*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D020820:Dyskinesias / Q000209:etiology / Q000628:therapy; D016332:Fetal Tissue Transplantation / Q000009:adverse effects / Q000379:methods / Q000639:trends*; D006085:Graft Survival; D006133:Growth Substances / Q000627:therapeutic use; D006801:Humans; D008636:Mesencephalon / Q000637:transplantation*; D019636:Neurodegenerative Diseases / Q000601:surgery; D009474:Neurons / Q000637:transplantation*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000601:surgery*; D013119:Spinal Cord Injuries / Q000601:surgery
D006133:Growth Substances; D004298:Dopamine