Feasibility of Intranasal Delivery of GDNF for Parkinson's Disease
Rapid Response Innovation Awards, 2007
The research from this grant has continued with the supplementary grant:
Glial cell line-derived neurotrophic factor (GDNF) is a small protein that potently promotes the survival of many types of neurons. The therapeutic potential of GDNF for Parkinson’s disease remains unfulfilled due to obstacles in its delivery to the brain. The goal of this research is to determine if GDNF can be given intranasally and reach the brain to protect dopamine neurons from the neurotoxin 6-hydroxydopamine (6-OHDA), a standard pre-clinical model of Parkinson’s disease. We will also test whether lipid vesicles incorporating GDNF can improve its transport to brain and increase its neuroprotective effect in rats.
We will first determine if GDNF is detectable in a rat's brain after intranasal administration. GDNF will be labeled with a radioactive tracer or a fluorescent tag and its distribution in the brain will be studied. Then 4 experiments will be done to look for evidence of neuroprotective effects of intranasal GDNF. The first will determine the maximum protection of dopamine neurons achievable with a single dose of GDNF in the pre-clinical model. The second study will examine the effects of multiple intranasal doses of GDNF given before, at the same time as, and after injection of 6-OHDA. The third experiment will test a range of GDNF doses to define the maximum and minimum neuroprotective effects. The final study will determine if intranasal GDNF increases the size and dopamine synthetic capacity of brain dopamine neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
GDNF cannot enter the brain after systemic administration, and the surgery to inject it directly into brain is too invasive for many patients. If nasal administration of GDNF is successful in protecting dopamine neurons in the rat and in other animal models of Parkinson’s disease, it may be developed as a therapy for patients.
Our research is a feasibility study to determine if the intranasal route can deliver sufficient amounts of GDNF to brain to protect dopamine neurons from the neurotoxic effects of 6-OHDA in rats, and to determine if a liposomal formulation provides greater neuroprotection than GDNF in solution. If the results are positive, intranasal GDNF may become an effective, patient controlled means of harnessing the therapeutic effects of GDNF for patients with Parkinson’s disease.
Dr. Waszczak demonstrated proof of concept for nasal delivery of GDNF into striatum and received supplemental funding for additional studies to determine whether nasal delivery is a practical approach for therapeutic delivery of GDNF.
Professor of Pharmacology, Department of Pharmaceutical Sciences at Bouve College of Health Sciences, Northeastern University
Location: Boston, Massachusetts, United States
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