Applying epigenetic modifying drugs to treat Friedreich's Ataxia

Lead Research Organisation: Medical Research Council
Department Name: UNLISTED

Abstract

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Technical Summary

We have recently shown that the GAA-triplet-repeat that pathologically expands and silences the frataxin (FXN) gene in the commonest autosomal recessive ataxia, Friedreich's Ataxia (FRDA), mediates transgene silencing in a manner reminiscent of chromatin-mediated silencing (Saveliev et al., 2003). This has led to the development of HDAC inhibitors (HDACis) which can upregulate frataxin (Festenstein, 2006; Herman et al., 2006) and are therefore potential treatments for this, as yet, untreatable and devastating condition. This proposal is to take forward a particular HDACi, known as compound z (due to patent restrictions), which we have found to be effective in up-regulating frataxin greater than 2-fold in lymphoblastoid cell lines and primary cells from patients with FRDA. Direct comparison with the HDACi, 4b, shows it to be more effective and it is certainly less toxic. As compound z has already been shown to have an excellent safety profile in humans and to cross the blood brain barrier, it has clear potential as a therapy for FRDA. We will now investigate its effects in humanised mouse models of FRDA. Thus, we will treat mice with the inhibitor and analyse the tissues that are characteristically affected by FRDA, such studies are clearly not possible in humans. Tissues will be analysed for FXN expression, FXN chromatin structure and for pathological changes. The mice will also be crossed to epigenetic-modifier mice to further dissect the mechanism of silencing and mechanism of action of this and other potential novel treatments at the chromatin/transcriptional level. FRDA can therefore be seen as a prototypic disease in which gene-silencing is the cause. We are well-placed to undertake this study as all the necessary techniques are already well established in the lab. Moreover, the CSC has a critical mass of researchers interested in epigenetics making this an ideal environment to pursue these studies. Compound z has a real possibility to become a treatment for FRDA, this study will go a long way to developing this potential.

Publications

10 25 50
 
Description FindaCure project to fund rare disease research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a guidance/advisory committee
 
Description A randomized double-blind placebo-controlled parallel-group multi-centre study of the efficacy and safety of nicotinamide in patients with Friedreich's ataxia (NICOFA)
Amount € 1,700,000 (EUR)
Organisation E-Rare 
Sector Public
Country France
Start 09/2017 
End 10/2020
 
Description BRC Imperial
Amount £140,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Public
Country United Kingdom
Start 06/2013 
End 12/2014
 
Description EC FP7 (EFACTS)
Amount £513,746 (GBP)
Funding ID 242193 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 04/2010 
End 04/2015
 
Description Efficacy and Mechanism Evaluation Programme NIHR/MRC EME Project:The UK arm of a multi-centre study of the efficacy and safety of nicotinamide in patients with Friedreich's ataxia (NICOFA)
Amount £900,000 (GBP)
Funding ID EME Project:17/90/01 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Public
Country United Kingdom
Start 03/2019 
End 10/2022
 
Description GMEC Rare Disease Consortium Pfizer
Amount £275,000 (GBP)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 03/2015 
End 03/2018
 
Description Research Grant
Amount $50,000 (USD)
Organisation Friedreich's Ataxia Research Alliance 
Sector Charity/Non Profit
Country United States
Start 12/2016 
End 12/2018
 
Description Response mode project grant
Amount £863,446 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2012 
End 09/2016
 
Description Rutherford Innovation Fellowship
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2017 
End 11/2019
 
Description Translational Project Grant Freidreich's ataxia
Amount £118,000 (GBP)
Organisation Ataxia UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 12/2013
 
Description Wellcome Trust Clinical Training Fellowship
Amount £247,000 (GBP)
Funding ID P48395 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 10/2016
 
Title FRDA cohort 
Description Set-up database for patients suffering from Friedreich's ataxia 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Obtained PBLs, chromatin and RNA inorder to perform epigenotype/phenotype correlations. 
 
Title Motion Capture Suit analytics 
Description Developing methodology to analyse behaviourmetric data in Friedreich's ataxia 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact The main impact promises to shorten the length of clinical trials by providing a more robust biomarker for disease progression by measuring movements during everyday living. 
 
Description Ataxia UK 
Organisation Ataxia UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Performed Pilot study funded by Ataxia UK together with NIHR. Involved in PPP to design current clinical trial and contribute to patient travel costs. Took part in meetings with patients to discuss research. Webnairs jointly organised with FARA.
Collaborator Contribution Organised patient responses to trial design
Impact EME grant for clinical efficacy of nicotinamide in Friedreich's ataxia
Start Year 2012
 
Description Clinical Study on FRDA 
Organisation National Hospital for Neurology and Neurosurgery
Country United Kingdom 
Sector Hospitals 
PI Contribution Established a proof-of-concept clinical study (funded by Ataxia UK) following our DPFS grant which demonstrated proof-of-concept in model systems. The clinical study is to establish whether an HDACi can upregulate the aberrantly silenced Frataxin gene in Friedreich's ataxia
Collaborator Contribution Provided staff, facilities and expertise of the Wellcome Trust Clinical Research Facility at the Hammersmith Hospital
Impact Ongoing clinical study, not yet complete
Start Year 2011
 
Description Clinical Study on FRDA 
Organisation Wellcome Trust
Department Wellcome Trust Clinical Research Facility
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Established a proof-of-concept clinical study (funded by Ataxia UK) following our DPFS grant which demonstrated proof-of-concept in model systems. The clinical study is to establish whether an HDACi can upregulate the aberrantly silenced Frataxin gene in Friedreich's ataxia
Collaborator Contribution Provided staff, facilities and expertise of the Wellcome Trust Clinical Research Facility at the Hammersmith Hospital
Impact Ongoing clinical study, not yet complete
Start Year 2011
 
Description EFACTS 
Organisation European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution The current project emerged from this EU Network of excellence. Several of the members across europe continue to participate in the study which grew out of a natural history study on Friedreich's ataxia.
Collaborator Contribution Members contribute to the clinical project through E-rare funding stream. NICOFA Trial is coordinated in Germany (Aachen). We pro
Impact The protocol for NICOFA was published 2019 - included in publications
Start Year 2012
 
Description Findacure 
Organisation Findacure
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Investigation with Findacure to calculate the cost benefits of reversing pathology in Friedreich's ataxia in order to make the case for funding a clinical trial of a novel disease modifying strategy in this disease
Collaborator Contribution Our collaborators provided methodology to model the economics of costs for looking after patients with Friedreich's ataxia
Impact This is a mutli-disciplinary projkect pulling together economics and health researchers
Start Year 2016
 
Description GMEC Rare Disease Consortium 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Friedreich's ataxia research on novel therapeutics
Collaborator Contribution Collaboration between Oxford University, UCL and Imperial on clinical and basic research aspects of Friedreich's ataxia
Impact Mitochondrial funcction, FXN gene regulation, epigenetics
Start Year 2015
 
Description Imperial College Clinical Research Facility 
Organisation Imperial College London
Department NIHR/Wellcome Trust Imperial Clinical Research Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution Conducted pilot study which seeded present study for clinical efficacy of nicotinamide in Friedreich's ataxia
Collaborator Contribution Enabled patients to be studied contribution of infrastructure for this complex study into clinical efficacy of nicotinamide in Friedreich's ataxia
Impact Libri et al Lancet 2014 - see publications. NIHR/MRC EME grant funding
Start Year 2012
 
Description NICOFA -E-rare funding for randomised controlled study for nicotinamide in Friedreich's ataxia 
Organisation University Hospital Aachen
Country Germany 
Sector Hospitals 
PI Contribution We have discovered that the aberrant gene silencing that occurs in Friedreich's ataxia causing the disease can be overcome in patients. This suggests that long-term treatment with nicotinamide would be expected to ameliorate disease progression in this frequently devastating and, so far, incurable disease. This study which was published in the Lancet has seeded further collaborations across EUrope to secure enough patients for a placebo controlled study.
Collaborator Contribution The partners have secured funding from a transnational E-rare funded collaboration. We are seeking funding from the MRC/NIHR EME scheme to fund the UK arm of the controlled trial.
Impact E-rare funding granted. EME proposal - full proposal invited.
Start Year 2016
 
Description UCLH NICOFA arm 
Organisation National Hospital for Neurology and Neurosurgery
Country United Kingdom 
Sector Hospitals 
PI Contribution Demonstrated that nicotinamide could upregulate the aberrantly silenced Frataxin gene in Friedreich's ataxia (Lancet 2014).
Collaborator Contribution Provision of patients, design of protocol.
Impact Pilot study (Lancet 2014) and Human Mol. Genet paper (2013) seeded EME NICOFA study for clinical efficacy of nicotinamide in slowing progression of Friedreich's ataxia
Start Year 2012
 
Title Identified potential therapeutic targets and therapies for Friedreich's ataxia 
Description We have found that particular histone deacetylase inhibitors can upregulate the aberrantly silenced Frataxin gene which is repressed in Friedreich's ataxia. 
IP Reference  
Protection Protection not required
Year Protection Granted 2008
Licensed No
Impact This has resulted in ourselves and opthers developing novel therapeutics which are undergoing testing in mouse models for Friedreich's ataxia.
 
Title HDACi therapy for FRDA 
Description Identification of an HDAC inhibitor that can upregulate Frataxin in cells from patients with Friedreich's ataxia 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact Potential as a therapeutic for Friedreich's ataxia which is currently incurable 
 
Description "Key Role for HUSH in Triplet-Repeat Silencing in Disease?" GRC conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact High level meeting recognising significance of work and enabling collaborations
Year(s) Of Engagement Activity 2019
URL https://www.grc.org/epigenetics-conference/2019/
 
Description International ataxia research conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Using induced pluripotent stem cell derived cardiomyocytes as a model to study Friedreich's ataxia - Poster presentation. Considerable interest from the audience which consisted of internationally recognised scientists and their teams as well as the leading charities supporting ataxia research
Year(s) Of Engagement Activity 2022
URL https://ataxiacongress.org/abstracts.htm
 
Description Invited Speaker at Ataxia Telangectasia meeting Napoli 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Excellent Scientific and clinical meeting on this subject - I gave a talk on machine learning analysis of movement in patients and was invited to take part in funding strategy meetin
Year(s) Of Engagement Activity 2018
URL http://www.centercongressi.com/ATconference2018/
 
Description Symposium on epigenetics and disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact approx. 250 people attended a vibrant and fascinating meeting on the interface between epigenetics and understanding disease

Experts in the field holding an open scientific meeting fostering science and public engagement
Year(s) Of Engagement Activity 2013
URL http://www.college-de-france.fr/site/en-jean-louis-mandel/seminar-2013-05-21-09h00.htm
 
Description TV documentary 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed for EU funded TV documentarty on Epigenetics

Communicated key ideas to a large lay audience
Year(s) Of Engagement Activity 2009
 
Description TV-interview Dublin 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed at International conference for Friedreich's Ataxia

Raised the profile of the need for research in triplet-repeat diseases
Year(s) Of Engagement Activity 2008
 
Description Webinar Ataxia UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Triggered many questions and comments relating to the next stage of our research

After the webinar I was given advice from experts on how to conduct a clinical trial for efficay of our novel treatment for Friedreich's ataxia
Year(s) Of Engagement Activity 2014
 
Description Webinar Friedreich's ataxia research alliancce 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact Feedback following publication of Lancet paper on epigenetic therapy for Friedreich's ataxia
Year(s) Of Engagement Activity 2014