Retinoid receptor modulators as novel disease-modifying therapeutics for Parkinson's disease

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Parkinson's disease (PD) is the fastest growing neurological disease. It is a complex condition with multiple inter-related pathomechanistic components. This makes tackling disease modification in PD a challenge. People with PD can access treatments that help relieve their motor symptoms. However, no treatment can yet preserve or repair the dopaminergic neurones that progressively degenerate. The mechanisms underlying this degeneration are complex: oxidative stress, mitochondrial dysfunction, proteasome dysfunction, ER stress, autophagy deficits, inflammation and excitotoxicity have all been implicated in the pathway towards apoptotic cell death. To date, pharmacological interference with these mechanisms individually has not yielded any agents that have proven successful in clinical trials. Retinoids regulate transcription of multiple protective genes involved in neuronal maintenance and development and as such are proposed as a promising target for disease modification in neurodegenerative disease like PD (Clark et al., 2020). To date, there is limited direct information on whether dysfunctional retinoid signalling is also a contributing causal factor in the pathogenesis of PD. However, their pharmacological profile alone provides a strong rationale for targeting this system to achieve neuroprotection and repair in PD. Indeed, retinoid acid itself prevents dopaminergic degeneration in the MPTP-treated mouse model of PD. However, this is not viable for clinical use because its action on retinoid X receptors produces unwanted adverse effects. To address this, Nevrargenics have developed an innovative dual-target (genomic and non-genomic) approach to create novel RAR-specific ligands. NVG0645 is one such potent ligand that has good ADMET qualities and produces multiple actions in-vitro that are compatible with reversing PD pathology including: anti-inflammatory; anti-excitotoxic; induction of neuroprotective genes; neurite extension (Khatib et al., 2019). In preliminary experiments, we showed that NVG0645 could protect against dopamine neuron degeneration and motor impairment in the 6-OHDA lesioned rat. In this project we will gather evidence supporting the beneficial effects of the RAR modulators and fully characterise the detailed molecular signalling mechanisms underpinning these effects. We predict RAR-modulators will provide neuroprotection, neuroplasticity and neurorepair to aid symptom relief. We will also explore the status of RAR systems in PD human brain. Overall, these studies will support progression of this class of RAR-M into clinical studies. There are 5 key aims to this project, embellished on in the next section. AIM 1: To determine the effective dosing regimen of the lead RAR-Ms for driving RAR signalling AIM 2: To establish the neuroprotective efficacy of RAR-Ms in the 6-OHDA lesioned rat model of PD and define the underlying mechanisms. AIM 3: To develop understanding of the translational steps in a drug discovery programme. AIM 4: To establish the ability of the best RAR-M to repair an established or developing lesion in 6-OHDA rat model and an alpha-synuclein expressing model of choice, and define underlying mechanisms AIM 5: To establish whether the retinoid system is impaired in PD patients