The benefits of fetal neural transplantation in primate Parkinson's models have been partially confirmed by studies in patients, but transplantation may have significant problems which should be addressed. Functional improvement appears variable, less effective in older patients, and incomplete in spite of some apparent increases in dopamine production. The hypotheses are that transplantation's limitations result from inadequate grafts, due to poor survival of implanted cells, lack of critical growth factors, or nonphysiological graft placements and distribution. This program proposes to test these hypotheses with strategies which may improve functional benefits--the primary outcome measure of all studies in MPTP parkinsonian monkeys. Project One targets early cell death after grafting, with strategies to reduce oxidant stress, hypoxia/ischemia, and apoptosis using cell adhesion factors, the lazaroid tirilizad mesylate, melatonin, vascular endothelial growth factor, and cAMP. Project Two focuses on growth factors produced by fetal striatum enriched in astrocyte progenitor cells, or the growth factor, GDNF, delivered from encapsulated cells. An optimized method will be tested to determine benefits of combined methods in young adult and aged monkeys. Project Three aims to restore the relevant dopamine pathways by implantation of substantia nigra (SN) precursor tissue into SN and directing its outgrowth to the target areas, using co-grafted fetal striatal cells, or GDNF delivery. Duration of and stability of behavioral improvement, possible dyskinesias, or other toxic effects will be evaluated for three years and compared with striatal grafts. Quantitative behavioral effects will be correlated with biochemical and morphological measurements post-mortem. These studies may contribute to improving graft survival, reinnervation, and physiological restoration of the defective dopamine circuits and normalizing function. Although considerable preliminary work has been done in rodents, and because definitive controlled experiments with verifiable outcomes cannot be accomplished in humans, hypotheses and safety should be tested in the MPTP model in monkeys. The projects will be undertaken jointly by the program investigators, applying the resources of a unique primate transplantation laboratory (Core A) and shared outcome methodologies, all coordinated by a program support unit (Core B). Understanding of fetal precursor cell survival and outgrowth may also lead to improved understanding of the plasticity and function of other potential replacement cells, such as stem cells, and be relevant to other human neurodegenerative or traumatic conditions in addition to Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS044281-01A1
Application #
6671217
Study Section
Special Emphasis Panel (ZNS1-SRB-E (02))
Program Officer
Sheehy, Paul A
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2003-09-30
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$1,226,266
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Redmond Jr, D Eugene; McEntire, Caleb R S; Kingsbery, Joseph P et al. (2013) Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson's model. Mol Ther 21:2160-8
Redmond Jr, D Eugene; Evans, Lawrence (2012) Determination of fetal age by ultrasonography in St. Kitts green monkeys. Am J Primatol 74:433-41
Redmond Jr, D Eugene (2012) Using monkeys to understand and cure Parkinson disease. Hastings Cent Rep Suppl:S7-S11
DeMartelly, Victoria; Hurley, Patrick; Lawrence, Mathew et al. (2012) Comparison of fresh to fixed weights of the vervet monkey (Chlorocebus sabaeus) placenta and its relation to gestational age. J Med Primatol 41:158-62
Morrow, B A; Roth, R H; Redmond Jr, D E et al. (2012) Susceptibility to a parkinsonian toxin varies during primate development. Exp Neurol 235:273-81
Bloch, Jocelyne; Kaeser, Mélanie; Sadeghi, Yalda et al. (2011) Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J Comp Neurol 519:775-89
Hurley, P J; Elsworth, J D; Whittaker, M C et al. (2011) Aged monkeys as a partial model for Parkinson's disease. Pharmacol Biochem Behav 99:324-32
Morrow, B A; Roth, R H; Redmond, D E et al. (2011) Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease. Neuroscience 189:277-85
Redmond Jr, Donald Eugene; Weiss, Stephanie; Elsworth, John D et al. (2010) Cellular repair in the parkinsonian nonhuman primate brain. Rejuvenation Res 13:188-94
Markakis, Eleni A; Vives, Kenneth P; Bober, Jeremy et al. (2010) Comparative transduction efficiency of AAV vector serotypes 1-6 in the substantia nigra and striatum of the primate brain. Mol Ther 18:588-93

Showing the most recent 10 out of 16 publications