Localized delivery of proteins in the brain: can transport be customized?

Certain central nervous system (CNS) diseases are characterized by the degeneration of specific cell populations. One strategy for treating neurodegenerative diseases is long-term, controlled delivery of proteins such as epidermal growth factor (EGF) and nerve growth factor (NGF). Since proteins permeate through brain capillaries very slowly, local administration using polymeric implants, continuous infusion pumps, or transplanted, protein-secreting cells may be required to achieve therapeutic concentrations in the tissue. The efficiency of local distribution, and hence effectiveness of local therapy, depends on the rate of protein migration through tissue. The rate of dispersion of molecules in a quiescent, isotropic medium can be characterized by the molecular diffusion coefficient, D, which can be measured by techniques such as quantitative autoradiography, iontophoresis, and fluorescence photobleaching recovery (FPR). These methods are reviewed, with an emphasis on their application to measurement of D for proteins in the brain. Biophysical techniques yield quantitative descriptions of local protein distribution and may enable discrimination of mechanisms of protein transport in the brain. This capability suggests a new paradigm for design of protein therapies, in which proteins and delivery systems are collectively customized to provide sustained protein availability over predetermined volumes of tissue.