Adrenal medullary autografts into the basal ganglia of Cebus monkeys: injury-induced regeneration.
ABSTRACT Questions arising from recent clinical neural transplantation trials in Parkinson's disease have under-scored the necessity for a thorough experimental evaluation of the structural and functional consequences of this procedure. The present study investigated the neuroanatomical host reaction to intrastriatal implants in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Nine monkeys (Cebus apella) received intrastriatal implants using either a stereotactic approach with a silver tissue carrier or an open microsurgical procedure. Seven of these animals received intrastriatal adrenal medullary autografts, while two received control implants consisting of the tissue carrier alone. One month following transplantation, the hosts' brains were evaluated via immunohistochemical and routine histologic methods. In both MPTP-treated and normal monkeys, enhanced ipsilateral expression of tyrosine hydroxylase-like immunoreactive (TH-IR) fibers in the caudate nucleus was observed, despite minimal survival of adrenal chromaffin cells in the implants. The intensity of this response was greatest adjacent to the implant site, but a clearly increased degree of ipsilateral striatal fiber staining also could be seen several millimeters from the graft. TH-IR fibers also were more dense and of thicker caliber throughout the nigrostriatal and mesolimbic pathways ipsilateral to the implant. Control stereotactic implants, consisting of a silver tissue carrier alone, produced a similar enhancement of immunoreactive fibers, suggesting an induction of TH-IR fibers by the parenchymal injury produced during surgical implantation. There are two major hypotheses proposed to explain why adrenal medullary grafts may promote functional recovery in human parkinsonism: (1) replacement of lost striatal neurotransmitter (dopamine) by the viable grafted tissue, or (2) induction of recovery of remaining host dopaminergic systems by the implantation procedure. Our current data appear to support the latter.
SourceAvailable from: Howard Federoff[Show abstract] [Hide abstract]
ABSTRACT: The pharmaceutical industry's development of therapeutic medications for the treatment of Parkinson's disease (PD) endures, as a result of the continuing need for better agents, and the increased clinical demand due to the aging population. Each new drug offers advantages and disadvantages to patients when compared to other medical offerings or surgical options. Deep brain stimulation (DBS) has become a standard surgical remedy for the effective treatment of select patients with PD, for whom most drug regimens have failed or become refractory. Similar to DBS as a surgical option, gene therapy for the treatment of PD is evolving as a future option. In the four different PD gene therapy approaches that have reached clinical trials investigators have documented an excellent safety profile associated with the stereotactic delivery, viral vectors and doses utilized, and transgenes expressed. In this article, we review the clinically relevant gene therapy strategies for the treatment of PD, concentrating on the published preclinical and clinical results, and the likely mechanisms involved. Based on these presentations, we advance an analysis of how the nature of the gene therapy used may eventually expand the scope and utility for the management of PD.Pharmaceuticals 12/2012; 5(6):553-590. DOI:10.3390/ph5060553
Expert Opinion on Therapeutic Patents 03/2011; 2(10). DOI:10.1517/13543718.104.22.1681 · 3.44 Impact Factor