CoEN Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases.

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences

Abstract

Neurodegenerative diseases such as Alzheimer's (AD) and motor neuron disease (ALS/MND) cause cell death of different populations of nerve cells. These conditions are very distressing for sufferers and their families. There is a severe lack of treatments available to slow disease progression and clinical trials have had high failure rates partly because there is no way to demonstrate that a drug is reaching the nervous system in the right amounts to protect the nerve cells from injury. Although the underlying causes that trigger these diseases are complex (multiple genes and environmental factors), there is substantial overlap in the cell pathways that lead to neurodegeneration.
This project is focused on a master cellular pathway (sometimes called the programmed cell-life pathway) controlled by a molecule NRF2 that promotes cell survival in the face of stresses such as oxidative stress, inflammation, and failure of the energy-generating and protein quality-control pathways within neurons which are known to contribute to neurodegeneration. Our aim is to develop MRI imaging and body fluid markers to show NRF2-activating drugs working in the body. These results will be applied later in clinical trials to test the effectiveness of NRF2 activators for patients with MND and AD.

Technical Summary

There is an urgent need for effective neuroprotective therapies for neurodegenerative disorders including motor neuron disease and Alzheimer's disease. The heterogeneity and complexity of these disorders have proved major challenges for therapy development. However, in both disorders neuronal injury involves a combination of age-related attenuation of protective responses; oxidative stress; mitochondrial dysfunction; dysregulation of proteostasis and neuroinflammation. In the presence of such cellular stresses, an up-regulation of the NRF2 signalling pathway increases the expression of an array of cytoprotective genes. This response is attenuated during ageing and also in MND and AD, as well as in models of these disorders. Compelling evidence has emerged from robust model systems, with major contributions from the two teams underpinning this application, that NRF2 activation has positive benefits in protecting neurons from injury in MND and AD.

The overall objectives are to develop multiple biochemical, transcriptomic and imaging biomarkers in robust animal models of MND and AD and linked with evaluation in human biosamples and imaging studies, to determine target engagement and indices of therapeutic efficacy of two NRF2-activating compounds (S-apomorphine and dimethyl fumarate) for future translation into human experimental medicine studies. Such 'translational biomarkers' are regarded as critical parameters for successful drug development.

Planned Impact

We will conduct the first proteomic based study of treatment effect and oxidative protein modification in CSF of ALS patients. Currently multiple NRF2 activators are in clinical development and as far as we are aware, trials have moved forward without demonstrating target engagement in the CNS. Our methodology will be made widely available to any group wishing to take NRF2 activators into clinical development. A University of Sheffield spin-out, Keapstone Therapeutics (RJM and PJS founders) is in the early stages of developing novel NRF2 activators for ALS and Parkinson's disease. Other companies such as Reata Pharmaceuticals are developing NRF2 activators in trials of Friedreich's ataxia and an Australian academic clinical trial of Dimethyl Fumarate is planned in ALS. Given the high level of interest, we consider that the translational methodologies outlined here will be key in determining the success of this approach and extending our understanding of the NRF2 signalling pathway in therapy development for neurodegenerative diseases.

Publications

10 25 50
 
Description AMS horizon scanning workshop
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Article featuring the work carried out by my laboratory in the March issue of Scitech Europa (PanEuropeanNetwork) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The PanEuropean Network aims to provide news and developments from across the entire spectrum of the European science and technology community. I was invited to submit an article about the work my lab carries out with industry and the support of EU funding. The audience of the journal is composed of EU commissioners and policy makers as well as scientists and the wider audience.
Year(s) Of Engagement Activity 2018
URL http://edition.pagesuite-professional.co.uk/html5/reader/production/default.aspx?pubname=&edid=0e6f6...
 
Description Focus on ALS Symposium, Genoa Italy, September 2018. Opening plenary lecture. A translational neuroscience approach to improve outcomes in ALS/MND: The journey so far and future prospects. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact FOCUS ON ALS 2018 is an important scientific event organized jointly between the Italian association for ALS (AISLA) and the Italian Foundation for the research on ALS (AriSLA). I gave the opening Plenary lecture
Year(s) Of Engagement Activity 2018
URL http://www.simposiosla.it/focus-on-als-2018/
 
Description FutureNeuro Symposium, Dublin October 2018: Translating neurological research into clinical practice. Plenary lecture. A translational neuroscience approach to improve outcomes in ALS/MND: The journey so far and future prospects 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The SFI FutureNeuro Center All Ireland Clinical Conference brought together neurologists from Ireland to build a common understanding of how Translational Research can be progressed in Ireland in the neurological field. This event aimed to build capacity in neurological science based on current research findings and to increase the knowledge level by presentation from international and domestic experts in the field.
Year(s) Of Engagement Activity 2018
URL https://www.eventbrite.ie/e/futureneuro-all-ireland-clinical-conference-2018-tickets-48027266848#
 
Description Neurotherapeutics Symposium, Universities of Rochester and Florida, February 2018, Orlando USA. Understanding motor neuron disease: The path to treatment 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This symposium focuses on the process of testing new drugs for the management of neurologic diseases. It focuses on the fields of neuromuscular and movement disorders. One goal of the symposium is to support young investigators with mentoring opportunities.
Year(s) Of Engagement Activity 2018
URL https://neurology.ufl.edu/2017/12/01/neurotherapeutics-symposium-2018/
 
Description Talk at the SITraN Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A broad talk about mitochondrial drug screening in patient derived models of Parkinson's Disease.
Year(s) Of Engagement Activity 2017
 
Description Target validation in ALS/MND meeting, London April 2018. The Nrf2-ARE pathway as a therapeutic target in ALS/MND 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact .
Year(s) Of Engagement Activity 2018