We plan to deliver the neurotropic factor, nerve growth factor (NGF), to the central nervous system (CNS) by formation of a conjugate between NGF and an anti-transferrin receptor antibody. We have recently shown that the antibody to the transferrin receptor crosses the blood-brain barrier by selective transcytosis and is taken up in the brain parenchyma from the blood stream following intravenous administration. Several different types of conjugates of NGF using the anti-transferrin receptor antibody as a carrier will be constructed since release characteristics are dissimilar for different conjugates. The ability to deliver NGF to the CNS following intravenous administration will allow treatment of neurological conditions involving neural degeneration such as Alzheimer's disease, Huntington's disease, aging, and Parkinson's disease. In Phase I, the anti-transferrin-receptor antibody-NGF conjugates will be prepared, purified and characterized and the profile of delivery to the CNS will be determined using a rat model. In Phase II, we plan to improve our carrier system by increasing the targeting ability and by humanization of the anti-transferrin receptor antibody. We also plan to compare our improved conjugate with NGF (free) in pre-clinical toxicity and in vivo rodent models of neuronal aging and neuronal degeneration.
