SBIR-STTR Award

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

Nerve growth factor (NGF) has been shown in vitro and in vivo to support the growth of basal forebrain cholinergic neurons. In Alzheimer's Disease, these cells undergo significant degenerative changes which may be responsible for the cognitive and memory deficits associated with this disorder. Because of this, NGF has been proposed as a therapeutic for the treatment of Alzheimer's Disease. However, the therapeutic use of NGF is hampered by the lack of a non-invasive means of delivery to the brain. It is our goal to demonstrate that a carrier based drug delivery system can be used for the effective transport of NGF from the bloodstream to the brain parenchyma. This delivery system utilizes, as carrier molecules, monoclonal antibodies that bind to the transferrin receptor, which is found in abundance on the luminal surface of brain capillary endothelial cells, and undergo transcytosis across the blood-brain barrier via the receptor. During Phase I of this project, NGF will be conjugated to the carrier antibody and tested for biological activity in vitro and delivery to the brain in vivo using a rat model. The in vivo efficacy of the NGF delivered using this system will be examined during Phase II.Awardee's statement of the potential commercial applications of the research:Currently there are no effective therapeutics for the treatment of Alzheimer's Disease. The current treatment costs for patients with this disease are in the order of $40 to $65 billion per year. The research could make it possible to administer nerve growth factor, a potential therapeutic for Alzheimer's Disease, intravenously and have it reach its site of action within the brain. If successful, this would have a significant impact on the treatment of this disorder.National Institute of Neurological Disorders and Stroke (NINDS)