This grant builds upon the research from a prior grant: Feasibility of Intranasal Delivery of GDNF for Parkinson's Disease
Objective/Rationale:
GDNF, a naturally-occurring growth factor capable of protecting and promoting the survival of dopamine neurons, has great potential as a treatment for Parkinson’s disease. However, the delivery of GDNF to the brain has proven to be an insurmountable obstacle. With a Rapid Response Innovation Award from The Michael J. Fox Foundation, we showed that GDNF given intranasally reaches the brain in sufficient quantities to protect dopamine neurons from the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard pre-clinical model of Parkinson’s disease. We will now determine:
1) whether there are any disadvantages of this approach, such as nasal toxicity, and
2) how much GDNF reaches the target brain areas after intranasal administration.
Project Description:
The first AIM will examine whether there is nasal toxicity in rats after a single dose, or three daily doses, of intranasal GDNF. Biochemical markers of nasal damage and immune system activation will be measured in nasal fluid taken six hours and one day after the treatments. Tissues of the nose will also be examined microscopically for evidence of pathology. The second AIM will measure how much GDNF reaches the target brain areas, the substantia nigra and striatum, after intranasal administration. In some experiments, GDNF will be labeled with a radioactive tracer and the amount in different brain regions will be determined by counting the radioactivity present. We also plan to use a biochemical assay to measure the amount GDNF in the target areas after a series of increasing doses of unlabeled GDNF. Together, these two approaches should tell us how much GDNF gets to the striatum and substantia nigra after intranasal delivery to rats.
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. Intranasal administration is a novel delivery approach that may bypass these problems allowing enough GDNF to reach the brain to stop Parkinson’s disease progression. If this route of administration increases GDNF in the target brain areas without damaging nasal tissues, it may be developed as a therapy for patients.
Anticipated Outcome:
Before testing in humans, we must confirm that intranasal GDNF gets into the brain, and that it is both safe and effective in animals. We have already demonstrated effectiveness in a pre-clinical model of Parkinson’s disease. Now we will measure how much GDNF reaches target areas in the rat brain, and whether it will be safe to proceed toward clinical trials. Ultimately, intranasal GDNF may become an effective, patient-controlled means of harnessing the therapeutic effects of GDNF for patients with Parkinson’s disease.
Final Outcome
The results of this Drug Delivery 2008 project confirm and extend the conclusions reached under a previous 2007 Rapid Response Innovation Award. The research team has demonstrated that intranasal administration of GDNF has neuroprotective efficacy in a preclinical model of Parkinson’s disease, that the protein gets into the brain and reaches target structures (the striatum and substantia nigra) within an hour of nasal administration, and that the nasal route causes no apparent toxicity in the nose. Longer term efficacy and toxicology studies will be necessary in other relevant preclinical models before testing can be initiated in humans.
The results of this work strongly supports pursuit of intranasal administration as a promising approach for harvesting the therapeutic potential of GDNF. Such an approach could ultimately provide an effective, non-invasive means of delivering GDNF to the brain for the treatment of Parkinson’s disease.