Research Project
6946617
DESCRIPTION (provided by applicant): Many age-related anatomical atrophies and physiological degenerations occur in the human brain and, in particular, in the cortical surfaces. A particularly tragic yet often encountered endpoint of such processes is the development of Alzheimer's disease, with its layer-specific dendritic regression and loss of gray matter, which have been studied over many years. Among the several strategies proposed for treatment has been the delivery of neurotrophic factors into the affected regions and, specifically, the infusion of nerve growth factors into carefully targeted areas. One particular example of such a strategy might be the delivery of brain-derived neurotrophic factor (BDNF) into the parietal cortex. Similar strategies have also been suggested and tested preliminarily for the treated of amyotrophic lateral sclerosis. The limitations associated with intracerebroventricular and related infusions of growth factors in Alzheimer's patients, as compared to the promising results in certain limited trials of intraparenchyma/infusion call for the development of improved infusion protocols tailored precisely to the needs of cortical infusions. Successful attainment of a technique that results in what we may call "surface contoured distributions" (SCD's) within layers of cortex would perhaps also open the door to infusion therapies for diabetic neuropathies, Huntington's disease and other such syndromes and conditions. However, the focus of all clinical research into infusions into brain parenchyma has been either on filling volumes as for glioblastomas, or for very localized regions, e.g. cell slurries into the substantia nigra or the striate cortex. There is a need for an infusion delivery system or class of neurocatheters that has been engineered to optimize SCD delivery of agents into relatively large areas but within thin layers of cortical tissue or into planar or non-planar areas in the deeper structures of the brain. In line with this need, our particular objectives will then be to: 1. Examine the scientific and medical rationale underlying the need for SCD infusion strategies and suggest novel approaches to obtaining well-defined layers of distribution. 2. Generate a plan for obtaining a mathematical description of SCD infusion that is in keeping with existing theories of volume-producing infusions and that is amenable to implementation as a software-based treatment planning system. 3. Adapt to SCD infusion the existing in vitro gel models of CNS structures that are used for pre-clinical validation of theoretical models and for preliminary testing of neurocatheter performance characteristics. 4. Suggest the design of a neurocatheter or neurocatheter system that is optimized for use in SCD infusions. In Phase II or subsequent efforts, we will test the predictions of the models and simulations based on the hypotheses developed here, and evaluate the performance of SCD neurocatheters in an appropriate animal model.
