Objective/Rationale:
Sanofi-aventis has identified Nurr1 receptor agonists whose in vitro pharmacological activity, together with literature data, indicate that Nurr1 agonists could provide a novel disease-modifying therapy for Parkinson’s disease (PD). However, we have not yet been able to show clear in vivo pharmacological activity of our Nurr1 agonists. The objective is to test our most advanced Nurr1 agonist in new pre-clinical models of PD, in which Nurr1 agonists have not been previously tested, and which could be more suitable for evaluating this mechanism of action.
Project Description:
Nurr1 agonists will be tested in new pre-clinical models of PD in the laboratories of Ole Isacson (USA) and Anders Björklund (Sweden). The Isacson laboratory will use a “multiple hit” model in which DA neuronal loss in the substantia nigra is induced by a primary bacterial or viral inflammatory trigger which causes a cytokine storm that predisposes vulnerable DA neurons to subsequent oxidative stress (6-OHDA) and neurodegeneration. The Björklund laboratory will use a model in which targeted overexpression of human wild type alpha-synuclein in the nigrostriatal system induces progressive loss of DA neurons that correlates with increased cytokine production, motor deficits, impaired DA release/uptake and decreased Nurr1 expression. These models are suitable to examine the neuroprotection and anti-inflammatory properties of a Nurr1 agonist in response to pathological insults related to PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Nurr1 expression is reduced in affected dopamine neurons in PD patients. In addition, Nurr1 agonists have the potential to promote the survival of dopaminergic neurons and to inhibit neuroinflammation-dependent neuronal loss. This dual mechanism of action could provide a novel disease modifying therapy for PD.
Anticipated Outcome:
Positive results will reinforce the importance of Nurr1 as a target for PD therapy and will be used to support a new pre-clinical package for passage of a Nurr1 agonist into clinical development. Negative results will be interpreted to show that the hypothesis for Nurr1 agonists has not been validated with the available pre-clinical models and the Sanofi-aventis Nurr1 programme will be stopped.
Final Outcome
The goal of this project was to evaluate the ability of the Nurr1 agonist, SA00025, to protect against dopaminergic neuron degeneration in two preclinical models of PD based on a “multiple hit” pre-clinical model of inflammation and oxidative stress and a pre-clinical model overexpressing alpha-synuclein. Before evaluating the ability of SA00025 to protect against dopaminergic neuron loss, we confirmed Nurr1 target engagement in vivo with SA00025 by demonstrating its ability to increase the expression of Nurr1-dependent dopaminergic markers in the substantia nigra (SN) of pre-clinical models and to inhibit the expression of Nurr1-dependent inflammatory markers in the SN after injection of an inflammatory trigger (Poly I:C) or adeno-associated virus type 6-a-synuclein (AAV-alpha-synuclein). In the subsequent neuroprotection studies, SA00025 showed no significant effect on dopaminergic neuron degeneration in the alpha-synuclein model and showed significant protection against SN dopaminergic neuron loss in the neuroinflammation and oxidative stress model.