Objective/Rationale:
Parkinson's disease (PD) is caused by the degeneration of certain dopaminergic neurons in the brain. Neurotrophic factors like GDNF protect dopaminergic neurons from degenerating in animal models of PD, but have so far not worked in clinical trials. MANF is a new neurotrophic factor that is strongly indicated for PD. This project will compare MANF and GDNF in new animal models of PD to determine if MANF is likely to be more effective than GDNF in clinical trials for PD.
Project Description:
The cell bodies of the dopaminergic neurons that degenerate in the human brain and cause PD are located in the substantia nigra, and their terminals project to the putamen (called the striatum in rats). We will mimic the death of dopaminergic neurons in the human brain using the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively kill dopaminergic neurons. The animals will then be treated with GDNF or MANF to try to protect the dopaminergic neurons from degenerating. We will deliver MANF or GDNF to the striatum or substantia nigra in separate experiments, and directly compare the improvement of neurological deficits with the survival of dopaminergic neurons in the substantia nigra. This is one of the first projects to directly compare drug delivery to the substantia nigra versus the putamen.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The results of this project could open the way for patients with PD to be successfully treated with MANF and/or GDNF. So far, neurotrophic factors have been delivered to the putamen in clinical trials. New surgical techniques now make delivery to the small substantia nigra, located deep in the brain possible. Delivery to the substantia nigra could increase the chances of success of GDNF and MANF in future clinical trials.
Anticipated Outcome:
We expect to use the results of this project to prioritize available drugs, and improve the design of future clinical trials of neurotrophic factors for PD. First, is MANF less effective, as effective or more effective compared with GDNF as a treatment for PD? Second, what should be the target for the delivery of the drug, the putamen, the substantia nigra, or both? The investigators believe that neurotrophic factors to treat PD will be more effective when delivered to the substantia nigra.
Final Outcome
MANF is one of two new molecules (the other is CDNF) currently in pre-clinical development for the treatment of Parkinson's disease. In a recently completed pre-clinical model of Parkinson's disease funded by MJFF, MANF corrected the neurological deficits when it was given immediately after the animals became sick. MANF also corrected the neurological deficits when it was given three weeks after the models became sick. This means that MANF is able to prevent the death of healthy dopaminergic neurons, but also MANF can save dopaminergic neurons that are already dying. How do these results apply to human patients? The results suggest that in patients newly diagnosed with Parkinson's disease MANF might be able to save those dopaminergic neurons that are sick and dying, but not yet dead. These patients will likely get better sooner, and their recovery will also last for a longer time. It is much too soon to predict whether MANF will be able to cure Parkinson's disease. MANF is certainly one of the most promising molecules currently in development to treat this debilitating disease.
Presentations
1. To Sonofi-Aventis, South San Francisco, CA; September 21, 2011
MANF: A Protein Biologic with Multiple Indications; A Non-confidential Presentation to Sonofi-Aventis
By John Commissiong
The neuroprotection data from the MJFF project were used in this presentation.
2. To The Parkinson's Institute, Sunnyvale, CA; October 20, 2011
MANF: A Bifunctional Protein with Multiple Indications
By John Commissiong
The neuroprotection and neurorestoration data from the MJFF project were used in this presentation.