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

亨廷顿舞蹈病是一种致命的遗传性神经系统疾病。最早的症状通常是情绪或认知方面的细微问题，随后是缺乏协调性和步态不稳。随着病情的发展，抽搐的身体运动变得更加明显，伴随着智力下降和行为和精神问题。受影响的个体还会出现逐渐的体重下降和肌肉萎缩。这种疾病通常会持续几十年直至死亡。对某些症状有一些有效的治疗方法，但没有治愈方法可以阻止或减缓疾病的进展。HD的遗传性意味着受影响个体的孩子有50%的机会自己患上这种疾病。这种疾病是由一个编码一种叫做亨廷顿蛋白（HTT）的基因突变引起的。突变基因和正常基因之间的唯一区别是DNA序列CAG在其开始附近的重复次数增加。这会导致HTT蛋白中谷氨酰胺（一种氨基酸，蛋白质的组成部分）的数量增加，从而导致HTT蛋白在制造它的细胞中以一种异常的方式表现。犬尿氨酸途径（一种关键的代谢途径）的紊乱长期以来被认为与HD症状的发展有关。这一途径的中心控制点是犬尿氨酸3-单氧酶（KMO）。事实上，如果KMO的活性被药物或基因抑制，它会使通路正常化，保护敏感的神经细胞，改善果蝇和小鼠的疾病症状。值得注意的是，现有的KMO抑制药物不能进入大脑——或者显示出有限的外显率——这可能最终对临床试验很重要。此外，KMO抑制对大脑的影响及其功能尚不清楚，需要进一步探索。在最初的工作中，我们已经产生了转基因小鼠，它允许在大脑或血细胞中特异性地删除KMO。这将使我们能够确定大脑中的KMO与血液中的KMO的“基因抑制”是否能改善小鼠的HD症状，以及是否有一种方法能产生更有效的保护。我们还将探讨KMO抑制HD患者血细胞的后果，以及HD患者血液和脑脊液中犬尿氨酸途径的改变。总的来说，这项工作将阐明KMO抑制在HD中的治疗相关性，如果有希望的话，将最终促进未来的临床试验。

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.