CHARACTERISING KYNURENINE 3-MONOOXYGENASE (KMO) AS A THERAPEUTIC TARGET FOR HUNTINGTON'S DISEASE

Lead Research Organisation: University of Leicester
Department Name: Genetics

Abstract

Huntington's disease (HD) is a fatal, inherited neurological condition. The earliest symptoms are often subtle problems with mood or cognition, followed by a lack of coordination and an unsteady gait. As the disease progresses, jerky body movements become more apparent, along with a decline in mental abilities and behavioural and psychiatric problems. Affected individuals also suffer progressive weight loss and muscle wasting. The disease typically progresses over several decades until death. There are a few effective treatments for some of the symptoms, but there is no cure that will halt or slow progression of the disease. The inherited nature of HD means that the children of affected individuals have a 50% chance of developing the disease themselves. The disease is caused by a mutation in a single gene that encodes for a protein called huntingtin (HTT). The only difference between the mutated and normal versions of the gene is an increase in the number of repeats of the DNA sequence CAG close to its beginning. This causes an increase in the number of glutamines (an amino acid, the building blocks of proteins) in the HTT protein, which leads to the HTT protein behaving in an aberrant fashion in the cells in which it's made.

Disturbances in the kynurenine pathway - a key metabolic pathway - have long been implicated in the development of HD symptoms. A central control point in this pathway is the enzyme kynurenine 3-monoxygeanse (KMO). Indeed, if activity of KMO is inhibited with either drugs or using genetics, it normalizes the pathway and protects sensitive nerve cells and improves symptoms of disease in fruit flies and mice. Notably, the available KMO inhibiting drugs cannot enter the brain - or show limited penetrance - which may ultimately be important for clinical testing. In addition, the effects of KMO inhibition on the brain and its function are not understood, and need to be explored. In initial work we have generated transgenic mice which permit the deletion of KMO specifically in the brain or in blood cells. These will allow us to determine if "genetic inhibition" of KMO in the brain versus blood improves HD symptoms in mice, and if one approach yields more potent protection. We will also explore the consequence of KMO inhibition in in blood cells from HD patients, as well as alterations in the kynurenine pathway in both blood and cerebrospinal fluid from HD patients. In total, this work will clarify the therapeutic relevance of KMO inhibition in HD, which - if promising - will ultimately facilitate future clinical trials.

Technical Summary

Huntington's disease (HD) is an incurable, fatal neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin protein. A hallmark of HD is the perturbation of the kynurenine pathway (KP), such that there is an increase in neurotoxic metabolites (quinolinic acid; 3-hydroxykynurenine) relative to the neuroprotective metabolite (KYNA). The KP enzyme kynurenine 3-monooxygenase (KMO) plays a central role in the regulation of this pathway; indeed its inhibition leads to normalization of the pathway in HD models, and a shift towards neuroprotection. We have found that pharmacological KMO inhibition also ameliorates neurodegeneration and other disease-relevant phenotypes in models of HD, including fruit flies and mice, making KMO inhibition a promising candidate therapeutic strategy. Notably, KMO inhibition specifically in the blood of HD mice is efficacious, but it is not yet known whether inhibition in the CNS yields similar or enhanced levels of neuroprotection.

Here we propose to validate KMO inhibition as a therapeutic strategy for HD by a number of approaches. We will employ our recently developed KMO conditional knockout mice, which will be crossed to R6/2 mice to test the efficacy of KMO inhibition by genetic means. We will delete KMO either globally, or specifically in the periphery or CNS in order to dissect the differential effects of KMO inhibition in these regions. We will expand upon this work by testing KMO inhibition in myeloid cells derived from HD patients. In parallel with this work, we will employ genomics approaches to explore the biology underlying KMO inhibition in control and HD mice, as well as in myeloid cells from HD patients. Finally, we will explore the biological relevance of our preliminary findings that KMO and huntingtin interact physically at mitochondria. In total, this work will clarify the therapeutic relevance of KMO inhibition in HD, which - if promising - will help translation to the clinic.

Planned Impact

This proposal has direct implications for individuals suffering from Huntington's disease (HD), and their families. Though several drugs are available for symptomatic management of HD, no treatments are available that halt progression or onset of HD and very few new disease-modifying therapies are in the clinical pipeline. It is estimated that HD costs up to $1 billion per year in medical and nursing costs in the United States alone. Furthermore the common neurodegenerative disorders affect more than 700,000 people in the UK, and cases are predicted to double in the next 25 years, costing the UK economy a staggering £50 billion. Indeed, studies estimate that neurodegenerative disease already costs the UK economy more than cancer and heart disease combined. Thus, in addition to the obvious patient benefits, the identification of an effective treatment for HD and other neurodegenerative disorders could dramatically cut these expenditures world-wide.

The potential beneficiaries also include scientists and clinicians working on HD, as well as biotechnology and pharmaceutical companies with research and development and/or commercial interests in these areas. It will also have important implications for the potential development of a new therapeutic strategy in HD. The discovery of such therapies will be of considerable commercial interest to companies working in this area. For patients, we hope the work will form the basis of developing treatments for those who have developed or are likely to develop the disease. Significant breakthroughs in KMO-based therapies will provide hope to patients and families, and will encourage participation in clinical trials. Understanding the mechanistic underpinnings of the disease will assist in the development of treatments for the benefit of patients. More widely, the discovery of underlying pathogenic processes and/or therapeutic targets in one neurodegenerative disorder offers hope for researchers working on and patients affected b many others; and this is particularly the case with the kynurenine pathway, which has been implicated in the pathogenesis of several neurodegenerative diseases. Due to the likely irreversible nature of the neuronal loss during neurodegeneration, therapies need to target the pre-degenerative disease state. Research in HD, for which there is predictive genetic test that can establish with absolute certainty whether a person will develop the disease later in life, may form the basis of the development of preventative treatments in other neurodegenerative disorders.
 
Title 30D, 30N, 23+23, 2.0 by Phil Hackett 
Description Artist Phil Hackett has generated acetate sheets based upon research in our laboratory, under the supervision of Research Associate Dr Carlo Breda, as part of a "Brief Encounters" programme at the University of Leicester - which brings together artists and scientists. This artwork is currently on display in Leicester as part of British Science Week. 
Type Of Art Artwork 
Year Produced 2018 
Impact None to date. 
 
Description Collaboration with Prof Gillian Bates 
Organisation University College London
Department Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We are co-applicants/PIs on the MRC grant Characterising Kynurenine 3-Monooxygenase (KMO) as a therapeutic target for Huntington's disease.
Collaborator Contribution The Bates group is performing the mouse-related research for the proposal.
Impact None as of y et
Start Year 2016
 
Description Alzheimer's Awareness Event (Lecture), Fundraising Event for Alzheimer's Society, University of Leicester. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact This was part of series of talks organized by undergraduate students to raise money for the Alzheimer's Society.
Year(s) Of Engagement Activity 2018
 
Description Brain Awareness Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact My lecture was part of a wider Brain Awareness Day event which the University of Leicester organized. It was broadly advertised and well attended. My lecture served to spark many questions from the audience how basic research using disease models can lead to advances in medicine and treatment.

The talk led to increased interest in my research, and hopefully emphasized to the audience the translational benefits of our studies.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description GENIE Open Day Events, University of Leicester, UK 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Open day events organized by GENIE a CETL based at the University of Leicester. ~200 school children per event learning about DNA and genetics, and the use in medicine, etc.

Generated interested in genetics amongst the school children - with greater interest in GCSE and A-level science/biology.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description Inaugural Lecture, University of Leicester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was my inaugural lecture for promotion to professorship, which was a public lecture/event. A mix of individuals from the university and the local community attended. Estimate ~200 people attended.
Year(s) Of Engagement Activity 2017
 
Description Interview BBC East Midlands Today 2016 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I was interviewed on BBC East Midlands Today TV in response to a press release from the university about our 2016 PNAS paper. This show is broadcast in the East Midlands region. I received emails regarding and other questions regarding this news coverage.
Year(s) Of Engagement Activity 2016
 
Description Invited seminar, Cardiff University, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A research seminar to approximately 30 people.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Germany. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research seminar.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar, Center for Neuroscience and Cell Biology of the University of Coimbra, Coimbra, Portugal. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I presented two seminars on Huntington's disease and my research to postgraduate students as part of a course on neurological diseases.
Year(s) Of Engagement Activity 2016
 
Description Invited seminar, Center for Neuroscience and Cell Biology of the University of Coimbra, Coimbra, Portugal. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Research seminar to PhD students and other researchers. Approximately 25 in attendance.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar, Liverpool John Moores University, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A research seminar to approximately 20 people.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar, Living Systems Institute, University of Exeter, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research seminar.
Year(s) Of Engagement Activity 2018
 
Description Invited speaker, British Yeast Group Conference 2018, University of Leicester, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited talk at conference. Approximately 120 people in attendance.
Year(s) Of Engagement Activity 2018
 
Description Poster presentation at CHDI Therapeutics Conference, Palm Springs, CA Feb 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at research conference.
Year(s) Of Engagement Activity 2018
 
Description Research visit to my laboratory by Mayor of Oadby-Wigston 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact The mayor and his wife, along with a 6th form student with an interest in neurobiology, visited my laboratory and saw a demonstration. In addition, I presented a short 15 minute talk giving an overview of our research approach.
Year(s) Of Engagement Activity 2019
 
Description University Taster Days 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact ~100 A-level students contemplating Leicester for undergraduate studies, along with parents/relatives. These talks covered my research, and the students asked several relevant questions, and were interested in how this could tie into their 3rd projects. This has been done 8 times, 7 times in Leicester and once in London.

Impacts will be determined based upon potentially increased applications to the university for study.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description Visit from Mill Lodge Huntington's Disease Inpatient Unit team to our laboratory, Leicester, UK. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact We hosted a visit from the Mill Lodge Huntington's disease team to our laboratory. The activities included HD research talks from our team and a tour of the labs. We also held a discussion over lunch about a future visit to their site, as well additional activities that we can do together.
Year(s) Of Engagement Activity 2018
 
Description Visit to Mill Lodge Huntington's Disease Inpatient Unit, Narborough, UK. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Members of my team and I visit Mill Lodge to interact with the professionals there that are taking care of Huntington's individuals. We learned about their work, and had discussions about future projects/interactions that we can develop.
Year(s) Of Engagement Activity 2018