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

亨廷顿病(HD)是一种致命的遗传性神经疾病。最早的症状通常是情绪或认知方面的细微问题，其次是缺乏协调性和步态不稳。随着疾病的发展，剧烈的身体运动变得更加明显，伴随着精神能力的下降以及行为和精神问题。受影响的人还会逐渐减轻体重和肌肉萎缩。这种疾病通常会在几十年内发展，直到死亡。对于一些症状，有几种有效的治疗方法，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人的孩子有50%的机会自己患上这种疾病。这种疾病是由编码一种名为Huntingtin(HTT)的蛋白质的单一基因突变引起的。该基因的突变版本和正常版本之间的唯一区别是DNA序列CAG在接近其起始位置的重复次数增加。这会导致HTT蛋白中谷氨酸(一种氨基酸，蛋白质的组成成分)的数量增加，从而导致HTT蛋白在制造它的细胞中以异常的方式运行。犬尿氨酸途径的紊乱--一个关键的代谢途径--长期以来一直被认为与HD症状的发展有关。该途径中的一个中央控制点是犬尿氨酸3-单氧基酶(KMO)。事实上，如果KMO的活性被药物或遗传学抑制，它就会使这一途径正常化，保护敏感的神经细胞，并改善果蝇和小鼠的疾病症状。值得注意的是，现有的KMO抑制药物无法进入大脑--或表现出有限的外透性--这可能最终对临床测试很重要。此外，KMO抑制对大脑及其功能的影响还不清楚，需要探索。在最初的工作中，我们已经培育了转基因小鼠，可以在大脑或血细胞中特异性地删除KMO。这些将使我们能够确定大脑中对KMO的“基因抑制”是否改善了小鼠的HD症状，以及一种方法是否产生了更有效的保护。我们还将探讨HD患者血细胞中KMO抑制的后果，以及HD患者血液和脑脊液中犬尿氨酸途径的变化。总而言之，这项工作将澄清KMO抑制在HD中的治疗相关性，如果有希望的话，这最终将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.