Objective/Rationale:
GDNF is a naturally occurring protein in the brain that protects and rescues the part of the brain that degenerates in Parkinson’s disease (PD). However, GDNF does not cross the brain’s protective membrane, called the blood-brain barrier, or BBB. Owing to the BBB problem, prior attempts to treat PD patients with GDNF used a pump system that infused the GDNF directly into the brain. However, this approach did not allow for adequate delivery of GDNF to the target region of brain.
Project Description:
In this project, the GDNF will be delivered to the target region via transport across the BBB, following a non-invasive intravenous administration. To enable transport across the BBB, the GDNF is re-engineered with the molecular Trojan horse technology. The GDNF is fused to a genetically engineered monoclonal antibody, which crosses the BBB via endogenous transport systems. The antibody acts as a molecular Trojan horse, and ferries the attached GDNF across the BBB, from blood, to the target site in brain. The GDNF-antibody combination is a combination molecule, also called a fusion protein. Following manufacture of the new drug, the efficacy of intravenous GDNF-fusion protein in a primate model of PD will be evaluated. In parallel, the potential toxicity of intravenous GDNF-fusion protein will be tested in primates.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The completion of this project will provide the basis for going forward with the necessary work that enables submission of an IND to the FDA, to begin clinical trials for testing the GDNF-fusion protein as a new treatment for PD. GDNF-fusion protein will be a first in class medicine for PD. GDNF-fusion protein is the first time a neuroprotective molecule has been re-engineered to enable transport across the human BBB.
Anticipated Outcome:
An experimental form of PD will be induced in primates. The animals will then be treated with either a placebo, or repeat injections of GDNF-fusion protein. During the course of treatment, the animals will be tested for PD signs and symptoms. The brain chemistry of the animals will then be examined. The study hopes to demonstrate that the degeneration of PD is halted by the repeat administration of GDNF-fusion protein, and that delivery of GDNF across the BBB is beneficial in PD.