Synthetic Retinoids for the Treatment of Neurodegenerative Diseases

Durham University Background
Many conditions and diseases are mediated by retinoic acid signalling, with several of these being neurodegenerative diseases e.g. motor neuron disease or amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS). These diseases affect millions of people throughout the World, and seriously impact a person’s ability to carry out normal day-to-day activities.
For the majority of cases the current treatments for ALS only produce a slowing in the decline with a life extension of months and are unable to reverse the damage that is already done. This is also the case for the treatments of other neurodegenerative diseases; there is a clear need for more effective treatments and therapies.
Technology Overview
Retinoids are a class of compounds derived from vitamin A (retinol) and its derivatives. These retinoids are an important class of signalling molecules and are involved in controlling many important biological pathways and cellular development.
Retinoic acid supports neuroplasticity which is essential for neural transmission, learning and memory and it has been shown that retinoic acid levels decline with age. That decline weakens neural transmission and cognitive function. Synthetic retinoids can boost the retinoic acid signal and can therefore potentially improve neural activity and cognition in those with ALS and the other neurodegenerative diseases.
Researchers at Durham University have developed novel synthetic retinoids that can be used in the treatment of RAR (retinoic acid receptor) mediated conditions, such as ALS and Alzheimer’s disease etc.. Through their innovative drug designs, they synthesized a range of potential novel retinoid drugs from which key drugs were identified that can selectively target both genomic and non-genomic pathways via the RARs (“dual-action” drugs). The result of the combined dual-mode effects of these novel drug designs is to trigger neurite outgrowth which is a viable model for neural regeneration, borne out in further models and ideally matched for treating the neural damage observed in ALS. Researchers are now developing a portfolio of effective neurodegenerative drugs, starting with ALS and moving on to Alzheimer’s and Parkinson’s, Spinal Muscular Atrophy and Multiple Sclerosis.
Further Details
The team has published widely on the novel underpinning science, with the following paper: being key to this work: Genomic and non-genomic Pathways are both crucial for peak induction of neurite outgrowth by retinoids, T. Khatib, P. Marini, S. Nunna, D. R. Chisholm, A. Whiting, C. Redfern, I. Greig and P. McCaffery, Cell Commun. Signal., 2019, DOI: 10.1186/s12964-019-0352-4.
Stage of Development
These studies resulted in a novel retinoid-based lead drug candidate which is a dual-acting compound with true potential for treating of ALS.
Following the identification of the lead compound, further work has been undertaken to turn that lead structure into a lead candidate for drug development, based upon the identification of ideal PK/ADMET and efficacy properties, as well as an ability pass through the blood brain barrier and build up in spinal fluids. These properties have created an ideal opportunity for a novel drug intervention into ALS (motor neuron disease), as a prelude to tackling wider neurodegenerative diseases.
Benefits

Dual action drugs uniquely targeting genomic and non-genomic pathways

Applications

A synthetic retinoic acid-mediated treatment for those affected by neurodegenerative conditions such as ALS, Alzheimer’s disease, Parkinson’s disease, and MS
Other retinoic acid mediated conditions could be treated with these synthetic retinoids
May have uses in the treatment of other conditions such as cancer and skin conditions

Opportunity
Durham University is seeking expressions of interest from industry partners with interest in the treatment of neurodegenerative conditions. A Durham spinout is being created to take forward the development of these drugs, through initial testing and trials.

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