Objective/Rationale:
Pharmacological methods to prevent or delay the degeneration of dopaminergic neurons in Parkinson’s disease (PD) are not available. We propose that Nurr1, a protein found in these neurons, could protect neurons from vanishing. Our rational is based on the fact that mutations found in patients reduce Nurr1 levels, or activity, and are associated with dopaminergic neuron loss. We hypothesize that increasing the activity or the expression levels of Nurr1 could be used for PD treatment.
Project Description:
This will be achieved using a “rational-drug-design” approach. We use specific computer software to design chemical compounds that will specifically affect the Nurr1 protein by binding to specific sites and thus increase its activity. We will check these compounds in cellular assays to verify their function and specificity. Ultimately, we will test them in mice. We will use existing genetically modified mouse strains that have features of PD, as well as create the features of the disease by treating mice with toxins that cause PD in people. Then, we will administer these compounds to these mice to evaluate their effects in preventing or delaying PD like symptoms. The pathological state of these animals we will be evaluated by biochemical and pathological analyses.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If successful, these experiments could have substantial effects on PD treatment. Development of drugs on this premise could stop or delay disease progression even in early stages. Additionally, since increased Nurr1 activity is expected to increase dopamine production, it is possible that such drugs could also lower L-DOPA requirements in later disease stages. Finally, in cell replacement therapies they could help increase the number of transplanted cells that become dopaminergic neurons.
Anticipated Outcome:
It is well established that partial loss of activity or levels of Nurr1 affects several pathways involved in PD pathogenesis, including protein toxicity and inflammation, and results in dopaminergic neuron death. Our experiments will clarify whether the logical assumption of increasing Nurr1 levels or activity can protect neurons from dying. In either case we will answer a critical question in proper drug target selection for PD treatment.
Progress Report
Pharmacological methods to prevent or delay the degeneration of dopaminergic neurons in Parkinson’s disease (PD) are not available. We propose that Nurr1, a protein found in these neurons, could protect them from vanishing. Our rationale is based on the fact that mutations found in PD patients reduce Nurr1 levels, or activity, and are associated with dopaminergic neuron loss. We hypothesize that increasing the activity or the expression levels of Nurr1 could be used for PD treatment. This will be achieved using a “rational-drug-design” approach. We use specific computer software to design chemical compounds that will specifically affect the Nurr1 protein by binding to specific sites and thus increase its activity. We have identified such a lead compound which, however, cannot reach the brain.
We have systematically modified the lead compound and determined the contribution of the different parts of the molecule in brain permeability, stability in vivo and efficacy in vitro. Currently, high brain permeability (experimentally determined B/P=1.5 while the lead compound B/P=0.02) has been achieved at the expense of activity. To bypass this issue we have synthesized a pro-drug whose analysis is pending. Additionally, analysis of more active and more stable analogs is also pending. If the pro-drug approach works in in vivo studies, we would be able to create additional pro-drugs and improve even further potential efficacy in PD animal models.
Final Outcome
Activation of a Nurr1 based complex by a synthetic ligand, indeed protects dopaminergic cell lines from MPP+ induced death. However, major problems of this compound prevented the full evaluation of this experimental pharmacological approach to be tested in pre-clinical models. We have extensively modified the molecule that had these properties in such a way as to generate a chemical that retains the neuroprotective properties of the original compound but it is also extremely stable and enters the brain of experimental models. Administration of the compound in pre-clinical models is well tolerated and currently we are analyzing its effect on pre-clinical models of Parkinson’s disease.