Neurotrophins are produced by cells in the nervous system; each protein regulates function and survival in subpopulations of neurons. Cell culture and animal models suggest that neurotrophins can protect neurons from death, influence differentiation, and induce plasticity. As a consequence, neurotrophins are promising candidates for treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Unfortunately, neurotrophins are not easily administered, presenting a major obstacle to human clinical applications. Neurotrophins have short half-lives in plasma, and transport through the blood-brain barrier is severely limited. In addition, neurotrophins are activate at a number of tissue sites, resulting in toxicity when systematically administered. Retrograde transport is an important mechanism for endogenous neurotrophin activity; it now appears, however, that retrograde transport is only one of several mechanisms for neurotrophin movement in the rain. In addition, a few recent studies suggest that the diffusion of exogenous neurotrophin through the extracellular space may be extremely limited (due to binding of neurotrophins to local protein receptors), presenting a new obstacle of neurotrophin delivery. At present, with the exception of retrograde transport, little is known about the mechanisms for neurotrophin movement and metabolism through the nervous system. Therefore we propose an integrated program of study with two major objectives: 1) development of polymeric delivery systems capable of providing controlled release of biologically active neurotrophins to localized regions of the brain over an extended period of time, and 2) characterization of the mechanisms of local transport and elimination for neurotrophins delivered to sites in the nervous system. We have three specific aims: 1) to examine the delivery and local transport of neurotrophins with in vitro assays systems that resemble tissue; ii) to determine the mechanisms of transport and elimination for neurotrophins administered by delivery systems in the CNS; and iii) to examine the limits of direct, intraparenchymal delivery for constructing concentration fields in the brain. We envision a new clinical approach (called pharmacotectonics) in which arrays of protein sources are strategically placed in the CNS; imaging techniques are used to create templates of treatment regions and models of drug distribution from each source are used to predict neurotrophin concentration fields that match the desired template.
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| Stroh, Mark; Zipfel, Warren R; Williams, Rebecca M et al. (2003) Diffusion of nerve growth factor in rat striatum as determined by multiphoton microscopy. Biophys J 85:581-8 |
| Mahoney, M J; Saltzman, W M (2001) Transplantation of brain cells assembled around a programmable synthetic microenvironment. Nat Biotechnol 19:934-9 |
