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

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.

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.

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.