Targeted Neurotrophin Drug Development in Parkinson's Disease

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a severe degenerative condition of the brain that affects 1 million people in the U.S. PD is caused by the progressive neurodegeneration of the nigral-striatal tract in brain. The brain produ ces endogenous neurotrophins that protect the dopaminergic neurons of the nigral-striatal tract. However, neurotrophins, like other large molecule neurotherapeutics, do not cross the blood-brain barrier (BBB) in vivo. Past attempts to deliver neurotrophins to the brain of people with PD have employed both intra-cerebroventricular (ICV) infusion and convection-enhanced diffusion (CED). Both approaches involve local, trans-cranial delivery to the brain following a neurosurgical procedure, and both approaches have been abandoned by the pharmaceutical industry. An alternative strategy is the re-formulation of the neurotrophin therapeutic to enable transport across the BBB, so that the neurotrophin can be administered by peripheral administration such as subcutan eous or intravenous injections. This research will produce a novel recombinant fusion protein, whereby a human neurotrophin is fused to a genetically engineered monoclonal antibody (MAb). The MAb crosses the BBB via receptor- mediated transport (RMT) on an endogenous BBB receptor. The MAb acts as a molecular Trojan horse (MTH), and ferries across the BBB the attached neurotrophin. The neurotrophin is then able to activate the neuronal neurotrophin receptor in brain behind the BBB. The fusion protein will be engineered so that both parts of the fusion protein, the MAb part, and the neurotrophin part, maintain high biological activity for the respective target receptors, ie, the BBB receptor and the neuronal receptor. The goal of this research plan is to first express the MAb-neurotrophin fusion gene in a permanently transfected host cell, and then purify the fusion protein to enable in vivo pharmacokinetics and brain uptake measurements in the adult primate. The bi-functionality of the fusion protein will then be verified with assays that test both binding to the BBB receptor and the neuronal receptor. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) affects 1 million people in the U.S., and is a severe degenerative disease of the brain. The disease is caused by the loss of brain cells in a region of the brain called the striatum. The brain produces a protein, called a neurotrophin, which results in protection of the striatum. However, neurotrophin drug therapy of PD cannot be developed, because the neurotrophi ns do not cross the blood-brain barrier (BBB). The present research will use genetic engineering to develop a PD-specific neurotrophin that can cross the BBB. This research will lead to a new neurotrophin treatment of PD, which can be administered by intra venous or subcutaneous administration.