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
Accogli A
(2023)
Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.
in Cerebellum (London, England)
Chisholm DR
(2019)
Fluorescent Retinoic Acid Analogues as Probes for Biochemical and Intracellular Characterization of Retinoid Signaling Pathways.
in ACS chemical biology
Clark JN
(2020)
Retinoic acid receptor-targeted drugs in neurodegenerative disease.
in Expert opinion on drug metabolism & toxicology
Gorberg V
(2022)
Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex
in Molecular Neurobiology
Haffez H
(2018)
Neurogenesis in Response to Synthetic Retinoids at Different Temporal Scales.
in Molecular neurobiology
Imoesi P
(2023)
Control by the brain of vitamin A homeostasis
in iScience
Imoesi PI
(2019)
Rapid Action of Retinoic Acid on the Hypothalamic Pituitary Adrenal Axis.
in Frontiers in molecular neuroscience
Khatib T
(2019)
A Bioluminescence Reporter Assay for Retinoic Acid Control of Translation of the GluR1 Subunit of the AMPA Glutamate Receptor.
in Molecular neurobiology
Khatib T
(2019)
Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids.
in Cell communication and signaling : CCS
Khatib T
(2020)
Decay in Retinoic Acid Signaling in Varied Models of Alzheimer's Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes.
in Journal of Alzheimer's disease : JAD
| 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 | £99,034 (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 | 04/2022 |
| 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 | 10/2022 |
| 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 | 04/2017 |
| 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 | 09/2018 |
| 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 | RAR-M THERAPEUTICS LIMITED |
| Description | RAR-M Therapeutics focuses on the development of dual-acting, Retinoic Acid Receptor-Modulators as lead potential drugs for developing a rational and effective new treatment regime for ALS and with the future goal of treatments for other neurodegenerative disorders such as Alzheimer's disease. |
| Year Established | 2019 |
| Impact | Company only started end of December 2019 |
| Website | https://rar-mtherapeutics.co.uk/ |
| Company Name | Lightox Ltd, Durham |
| Description | The company "Lightox" was spun out from the research of Prof. Andy Whiting and Dr. Carrie Ambler based, in part, on the research performed in the BBSRC follow on fund. Lightox was founded on a series of fluorescent retinoids synthesized by Prof. Whiting and tested for their biological function by Dr. Ambler and found to have cell killing activity when exposed to excitatory light. Working with the Aberdeen team, Lightox will lead the commercial development of the retinoids shown to have therapeutic activity in neurodegenerative disease through the development of further collaborative interactions, especially with big pharma. This will be both for Alzheimer's disease, the current focus of the project, as well the degenerative disease ALS, of next scientific focus. |
| Year Established | 2017 |
| Impact | None |
| Website | http://lightox.co.uk |
| 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 |