DELIVERY OF NERVE GROWTH FACTOR TO THE BRAIN

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 ANTIBODIESTHAT BIND TO THE TRANSFERRIN RECEPTOR, WHICH IS FOUND IN ABUNDANCE ON THE LUMINAL SURFACE OF BRAIN CAPILLARY E 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 ANTIBODYAND 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. 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 ANTIBODIESTHAT BIND TO THE TRANSFERRIN RECEPTOR, WHICH IS FOUND IN ABUNDANCE ON THE LUMINAL SURFACE OF BRAIN CAPILLARY E 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 ANTIBODYAND 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.