All-trans-retinoic acid (ATRA) is an endogenous signalling molecule that regulates transcription by activating RAR nuclear receptors. ATRA is used as a drug to treat skin disorders as well as a variety of cancers. ATRA is also potent in promoting neuronal survival and neurite outgrowth, suggesting potential as a therapy for improving cognition in dementia and other neurodegenerative disorders. This application is based upon the development and commercialisation of a series of synthetic RAR ligands which show a dramatic increase in potency in neurotrophic activity over ATRA, as well as pharmacokinetic and physicochemical advantages, which make them suitable for preclinical development.
ATRA has been proposed as a treatment for a number of neurodegenerative diseases, including Alzheimer’s disease (AD). Use of ATRA was inspired by the finding that endogenous ATRA levels decline in the ageing human and rodent brain. As ATRA supports neuronal survival and neuroplasticity, essential for learning and memory, this decline weakens cognitive function. Boosting the ATRA signal with ligands for RARs improves cognition in AD model mice, acting at multiple stages of the disease. Importantly, ATRA has an efficacious effect in multiple models of AD, also improving cognition and providing anti-inflammatory action in a diabetic model of AD. Hence RAR ligands may provide a treatment for AD and other neurodegenerative disorders. However the pipeline for new retinoid drugs is barely existent: ligands with high affinity and capacity to induce gene expression had already been developed and thus it was assumed that optimised ligands already existed. Our results, however, indicated that screening receptor affinity and genomic (gene regulatory) activity as the sole parameters to determine physiological potency was flawed because it ignored ligand ability to induce non-genomic signalling pathways acting via kinases. In contrast to the thousands of paper published on RAR function via regulation of gene expression, only a few dozen papers have been published on the non-genomic action of RAR. However the non-genomic capacity of RARs to regulate kinases, including ERK1/2, is proposed to be integral to some of the functions of RARs and ERK1/2 is already extensively characterised to be a key element in pathways controlling cell growth and neurite outgrowth. We hypothesised that characterising RAR ligands for both their genomic and non-genomic actions would reveal ligands specific for one route or the other, thus potentially allowing for certain therapeutic and toxic properties to be separated. Previously no such screen had been performed. Screening a limited series of genomically-characterised commercially-available retinoids did indeed demonstrate that several induced only one or the other pathway; unexpectedly, it was also found that retinoids that activate BOTH genomic and non-genomic were those with the highest activity in assays for neuronal survival and neurite outgrowth. Based on our studies, and optimisation of the balance between the genomic and non-genomic signalling, we have identified and developed a series of synthetic retinoids which show considerably increased affinity for each of the RARs with considerably enhanced activity as a promoter of neurite outgrowth.
In a focussed program supported by a BBSRC Follow-on Fund award, we are developing compounds based on their genomic vs non-genomic activity as well as their activity in assays directed towards AD therapeutics. This will improve the likelihood of identification of drugs that are beneficial in AD and other neurodegenerative disorders.
Project Team: Professor Peter McCaffery, Dr Iain Greig, Professor Bettina Platt, Professor Andy Whiting (Durham)