Argo Therapeutics GmbH
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We have developed a novel therapeutic for Parkinson's disease (PD) showing multiple both disease-modifying and symptomatic efficacy1. The target of our developing PD therapeutic is Nurr1, a nuclear receptor required for the development of dopaminergic neurons2 that has been implicated in both dopamine biosynthesis and dopaminergic neuron survival. Nurr1 was shown to be involved in the activation of tyrosine hydroxylase (TH)3 and GTP cyclohydrolase I (GCH1)4 that are critical enzymes for DA synthesis. Furthermore, Nurr1 decreased levels are strongly associated with PD and reduced dopaminergic neuron survival. Nurr1 mutations decreasing its mRNA were found in PD patients5 while Nurr1 protein levels are reduced in the SN of PD brains6. Nurr1 ablation in adult mice leads to loss of striatal dopamine and behavioral features of parkinsonism during aging7. Finally, reduced Nurr1 levels in mice result in increased microglial activation and augmented inflammatory response that is further amplified by astrocytes leading to death of neurons in SN8. Given the potential of Nurr1 to be a PD target, our rational was to pharmacologically activate it and then test its efficacy in PD models. However, Nurr1 lacks a classical ligand binding pocket. Since in midbrain dopaminergic neurons, Nurr1 forms heterodimers with RXRa, we postulated that targeting Nurr1:RXRa heterodimers with synthetic ligands that bind to the RXRa binding pocket could be a potential therapeutic strategy for PD. Indeed, we have developed Nurr1:RXRa selective compounds and validated their therapeutic potential in vivo. Importantly, we have shown that our ligands also apply to other therapeutic indications as well. We are currently further optimizing them to bring them to the clinic and deliver a novel treatment for Parkinson's and other brain diseases.
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