Effects of Recombinant CDNF Protein in Alpha-synuclein Model of Parkinson’s Disease in Pre-Clinical Models



Objective/Rationale:Neurotrophic factors have been explored as a novel treatment for Parkinson’s disease. Toxic effect of α-synucleinopathies, one of the hallmarks in PD pathophysiology, occurs in endoplasmic reticulum (ER) and α-synuclein accumulation leads to ER stress and contributes to neurodegeneration. Recent data about the mechanism of CDNF indicate that its neuroprotective effects are mediated by mechanisms involved in ER stress. This proposal studies the effectiveness of human CDNF protein in pre-clinical models of α-synuclein-induced dopamine neurondegeneration.

Project Description:
The neuroprotective effectiveness of intrastriatally delivered CDNF protein against neurodegeneration of nigral dopamine neurons in α-synucleipathies induced by α-synuclein expressing viral vectors will be studied. First, we will compare four different preparations of adeno-associated virus (AAV)-vectors expressing α-synuclein in their ability to induce neurodegeneration in substantia nigra. Amphetamine-induced rotation and cylinder test, as well tyrosine hydroxylase immunohistochemistry from striatum and substantia nigra, will be performed. CDNF protein or vehicle (PBS buffer solution) will be injected unilaterally at the dose of 10 μg into the striatum. The dose has been chosen based on previous studies. AAV-6 vector carrying human α-synuclein cDNA will be injected just above pre-clinical model substantia nigra one day later. Similar outcome measures as stated above will be used in the neuroprotection experiment.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our results show that CDNF is a potent treatment candidate to stop the progression of PD. Our main goal is to take CDNF to the clinic for the treatment of PD. To reach that goal this study will further clarify the pharmacodynamic action of CDNF in another pre-clinical model of PD. This study will further enable to predict the efficacy of CDNF in human PD patients.

Anticipated Outcome:
Neurotrophic factors GDNF and NRTN are in clinical trials for PD, but current results show their modest clinical benefit. One reason for this is poor diffusion of GDNF and NRTN in the brain. GDNF has no neuropoetective effecsts in α-synuclein overexpressing rat models of PD. CDNF diffuses significantly better in brain and is involved in protein folding and regulation of ER stress. We postulate that CDNF can assist α-synuclein folding and protect neurons against α-synucleopathies.
Gällande start-/slutdatum01/01/2013 → …