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.
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.
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 by 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.
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 by 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.
Publications
Zhang S
(2019)
A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites
in Communications Biology
Maddison DC
(2020)
A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.
in PLoS genetics
Bondulich MK
(2021)
Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington's disease.
in Scientific reports
Erhardt S
(2017)
Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.
in Biological psychiatry
Sathyasaikumar KV
(2018)
Assessing and Modulating Kynurenine Pathway Dynamics in Huntington's Disease: Focus on Kynurenine 3-Monooxygenase.
in Methods in molecular biology (Clifton, N.J.)
Spiers JG
(2019)
Drosophila Nrf2/Keap1 Mediated Redox Signaling Supports Synaptic Function and Longevity and Impacts on Circadian Activity.
in Frontiers in molecular neuroscience
Vicente Miranda H
(2016)
Glycation potentiates neurodegeneration in models of Huntington's disease.
in Scientific reports
Pido-Lopez J
(2019)
Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington's disease by etanercept treatment.
in Scientific reports
Swaih AM
(2022)
Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.
in Biomedicines
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 | 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017 |
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 | International Symposium on Flavins and Flavoproteins |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Research talk at the International Symposium on Flavins and Flavoproteins, which was held in Graz, Austria and feature speakers both in person and virtually. My talk was focused on our work with KMO and neurodegenerative disease, including Huntington's. The lecture was followed by questions from the audience. |
Year(s) Of Engagement Activity | 2021 |
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, CEDOC Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Seminar at the CEDOC Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal. ~100 people attended, which included academics, clinicians, postdoctoral researchers and postgraduate students. The seminar sparked questions and discussion, as well as potential for future collaborative research. |
Year(s) Of Engagement Activity | 2019 |
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 | Research seminar to PhD students and other researchers. Approximately 25 in attendance. |
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, 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 seminar, Maryland Psychiatric Research Center, University of Maryland Medical School, Baltimore, Maryland, USA. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk to researchers worked in a related area, where we are beginning collaborative work. The talk generated questions and discussion. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker (virtual), Virtual Symposium Series - Neurodegeneration in Flies, UCL Institute of Healthy Ageing, University College London, UK. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a virtual seminar as part of a series of events organised by UCL. After the presentation, questions from the audience were addressed. |
Year(s) Of Engagement Activity | 2022 |
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 | Invited speaker, The Midlands 3Rs Symposium 2022, University of Nottingham, Nottingham, UK. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | This was a talk delivered as part of the Midlands 3Rs Symposium. After the talk questions were answered from the audience. |
Year(s) Of Engagement Activity | 2022 |
Description | Keynote speaker at Macquarie Neurodegeneration Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a webinar hosted by Macquarie University in Sydney, Australia. The focus was on neurodegenerative diseases, and featured keynote speakers from several countries around the world. My talk sparked questions which were discussed. |
Year(s) Of Engagement Activity | 2020 |
Description | Pint of Science talk at "Matter Over Mind" event, Spirits Bar, Leicester, UK; "Brain puzzles: understanding neurodegenerative diseases" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | This was part of a "Pint of Science" event in which outreach talks on science are giving at local pubs, etc. I gave a talk on some of our research, but also highlight our general approach of using genetics and model organisms to study neurodegenerative disease. ~50-100 inviduals attend from the general public and from the University of Leicester. The talk sparked questions and discussion. |
Year(s) Of Engagement Activity | 2019 |
Description | Plenary seminar, 1st International Conference on Neuroprotection by Drugs, Nutraceuticals and Physical Activity, University of Bologna, Rimini, Italy. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was an invited plenary seminar at a conference, which was attended predominantly by ~150 academic researchers, postdoctoral researchers and postgraduate students. The talk sparked questions and discussion. |
Year(s) Of Engagement Activity | 2019 |
Description | Plenary seminar, Microbiology Society Annual Conference 2019, Belfast, UK. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This was a plenary seminar at the Microbiology Society Annual Conference 2019, Belfast, UK. The audience was approximately 100-120 people consisting of academics, postdoctoral researchers, postgraduate students and likely some members of industry. The seminar sparked questions and discussion. |
Year(s) Of Engagement Activity | 2019 |
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 | Science stand at Fruit Fly Festival, Leicestershire Huntington's Disease Service, Mill Lodge/Stewart House, Narborough, UK. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | As part of the Fruit Fly Festival organised by the Leicestershire Huntington's Disease Service (Mill Lodge/Stewart House, Narborough, UK) we ran a science stand that explained the basics of genetics and our approach to Huntington's related research using model systmes. The audience was primary patients, family members, care givers and practitioners. ~50 people attended. |
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 |