Discovery that a dual-action screen (genomic/non-genomic) identifies retinoic acid receptor ligands of highest neurotrophic potency

Lead Research Organisation: University of Aberdeen
Department Name: Sch of Medicine, Medical Sci & Nutrition

Abstract

The number of people in the UK suffering from diseases that accelerate the deterioration of the brain has shown a dramatic increase in recent years, with our ageing population and increasing life expectancy; however, there is a desperate lack of effective drugs to treat these diseases, which include Alzheimer's and Parkinson's. The retinoic acid receptor is a promising protective target for these diseases; this neuroprotective action is activated when the receptor binds a small lipid called a retinoid. We have discovered a new means for designing and identifying retinoids that switch on the receptor in a way that best maximises its protective action. We will develop new retinoids for their capacity to treat the damaging changes associated with Alzheimer's. We will form a company which will further develop and evaluate these compounds, to the stage that they can be licensed to pharma and taken into clinical trials, for the treatment of Alzheimer's and other neurodegenerative diseases.

Publications

10 25 50
 
Description Significant achievements of the project to date:
(i) Biological screening of 49 new and diverse compounds for their genomic and non-genomic activity
(ii) Development of a new non-genomic assay for RAR ligands which measures activity to promote translation (as described in "Research Tools & Methods")
(iii) Demonstration that genes and their corresponding proteins required for retinoic acid signalling are downregulated in several mouse models of Alzheimer's disease.
(iv) In addition to several new ligands with specific and novel activities, the project has identified two structurally RAR ligands with potent action in key areas, i.e. to regulate genes
promoting the non-amyloidogenic pathway, reducing neuroinflammation and promoting survival, suggesting their promise as therapeutics for Alzheimer's disease and potentially
other neurodegenerative diseases.
(v) Identification of a lead compound with good stability indicated by rodent and human liver microsome assay as well as high permeability and low efflux from assay with Madin
Darby canine kidney cells.
(vi) A series of in-vitro screens of the RAR ligands for effectiveness in ALS treatment showed promising results (a) inducing neurite outgrowth in human motor neurons from iPS cells,
(b) increasing gene expression of pro-survival and anti-inflammatory genes and (c) enhancing nerve-evoked muscle tension for both twitch and tetanus in electrophysiological
recordings when synaptic transmission is impaired.
Exploitation Route Development of new drugs for Alzheimer's disease, ALS and other neurodegenerative diseases
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Led to foundation of company Nevrargenics Ltd https://nevrargenics.com/
First Year Of Impact 2019
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description New section on "Molecular pharmacology of nuclear receptors and their role in health and disease" in Molecular Pharmacology MSc course
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Application of artificial intelligence-driven design of function-directed ligands for selective retinoic acid receptor binding
Amount £102,396 (GBP)
Funding ID BB/S507350/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description Development of RAR class ligands for treatment of Motor Neuron Disease
Amount £241,796 (GBP)
Funding ID 882-791 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2022 
End 03/2025
 
Description Discovery of retinoic acid receptor control of stress granules as a potential treatment for neurodegenerative disease
Amount £96,875 (GBP)
Funding ID PhD-CT-21-18 
Organisation The Cunningham Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2022 
End 09/2025
 
Description NHS Grampian Endowment Research Grant
Amount £12,000 (GBP)
Organisation NHS Grampian 
Department NHS Grampian Endowment Fund
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 09/2018
 
Description Northern Accelerator
Amount £35,000 (GBP)
Funding ID N/A 
Organisation United Kingdom Research and Innovation 
Department Northern Accelerator
Sector Charity/Non Profit
Country United Kingdom
Start 03/2019 
End 03/2020
 
Description Scottish PhD Research & Innovation Network Traineeships in Motorneuron Disease/Multiple Sclerosis
Amount £47,136 (GBP)
Organisation University of Edinburgh 
Department Edinburgh Neuroscience
Sector Academic/University
Country United Kingdom
Start 08/2018 
End 09/2020
 
Title Detection of RAR ligands in tissue 
Description We have developed a method to detect the RAR ligands in neural tissue. The assay is based on a retinoic acid reporter cell line we have previously used as a tool in a number of assays and have developed an effective technique where retinoids are solvent extracted from tissue and can be detected by these reporter cells. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact The technique is essential for the future stage of development of the project into animal models. 
 
Title Screen for translational regulation by retinoic acid receptors 
Description A novel system was designed to mimic what happens in the neurons during homeostatic plasticity. A bioluminescence reporter plasmid that expressed firefly luciferase under the control of the GluR1 5'UTR was constructed and introduced into SH-SY5Y cells. The cell line was then used to screen synthetic RAR ligands for their ability to increase AMPA receptor translation versus activation of gene transcription. 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? No  
Impact None 
 
Title Use of immunohistochemistry to detect regions of retinoic acid synthesis 
Description Retinoic acid itself is very difficult to detect by immunohistochemistry as there are few effective antibodies to this lipid and it can be difficult to fix in place in tissue. A set of retinaldehyde dehydrogenases (RALDHs) catalyze the last step of retinoic acid synthesis and their distribution can be used as a proxy for retinoic acid distribution. We have optimised methods to detect RALDHs in neuronal tissue and RALDH2 expression in the motor neurons of the spinal cord is used as a demonstration of the approach and we describe methods that can improve its effectiveness. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact 8 readers of this publication at this time. 
 
Title Database shared on Dropbox listing information on new RAR ligands 
Description A database is being shared on Dropbox that includes all information on the 66 new RAR ligands that have been generated as part of the project. This database includes all known chemicals and biological information that we have discovered on the 36 of these so far screened biologically. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact None 
 
Description Collaboration with Prof. Gareth Miles 
Organisation University of St Andrews
Department School of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration to study the action of retinoic acid to regulate the excitability of neurons in the spinal cord.
Collaborator Contribution Expertise in electrophysiological study of neurons
Impact No outputs yet from this collaboration. The study is not multi-disciplinary.
Start Year 2019
 
Description Work with Dr. Guy Bewick on amyotrophic lateral sclerosis 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of novel RAR ligands for study.
Collaborator Contribution Dr. Guy Bewick (https://www.abdn.ac.uk/ims/profiles/g.s.bewick) at Aberdeen is testing the influence of RAR ligands on the strength of the neuromuscular synapse as well as muscle tension in in-vitro preparations. These studies led to some positive results with a number of these ligands. Dr. Bewick's expertise in the establishment and maintenance of nerve-muscle signalling has led to recent papers in "Nature Communications" and "J. Neuroscience".
Impact No outcomes yet but promising preliminary data. The collaboration is multi-disciplinary bringing together synthetic chemistry and physiology.
Start Year 2017
 
Description Work with Professor Siddharthan Chandran testing RAR ligands on on amyotrophic lateral sclerosis iPS cells 
Organisation University of Edinburgh
Department Euan Macdonald Centre for Motor Neurone Disease Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of novel RAR ligands for study.
Collaborator Contribution Professor Siddharthan Chandran, Director of the Euan MacDonald Centre and Centre for Clinical Brain Sciences in Edinburgh is testing several RAR ligands for the capacity to induce neurite outgrowth in iPS cells derived from cells obtained from ALS patients.
Impact Studies are still in process
Start Year 2017
 
Title SYNTHETIC RETINOIDS FOR USE IN RAR MEDIATED CONDITIONS 
Description Generation of new RAR ligands for use in a range of disorders including neurodegenerative diseases. 
IP Reference US2019112272 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Creation of start up company RAR-M Therapeutics
 
Title SYNTHETIC RETINOIDS FOR USE IN RAR MEDIATED CONDITIONS 
Description There are described novel compounds of formula I: in which R1, R2, R3, R4, R5, X1 and X2 are each as herein defined, for use in the treatment or alleviation of an RAR mediated condition: and methods related thereto. 
IP Reference WO2017174999 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact None
 
Company Name LightOx 
Description LightOx develops light activated chemotherapy designed to treat early-stage oral cancer, with its technology also having applications as a research tool in imaging, therapeutics and assay binding. 
Year Established 2016 
Impact None
Website http://lightox.co.uk
 
Company Name Nevrargenics 
Description Nevrargenics discovers and develops pharmaceuticals for neurodegenerative diseases. 
Year Established 2019 
Impact Company only started end of December 2019
Website https://nevrargenics.com/
 
Description Aberdeen Doors Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentations on the brain and Alzheimer's disease at the 2017, 2018 and 2019 Aberdeen Doors Open Day.
Year(s) Of Engagement Activity 2017,2018,2019