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

描述犬尿氨酸 3-单加氧酶 (KMO) 作为亨廷顿病治疗靶点的特征

• 批准号: MR/N00373X/1
• 负责人: Flaviano Giorgini
• 金额: $ 102.53万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN00373X%2F1
• 关键词: CHARACTERISING; KYNURENINE; MONOOXYGENASE; KMO; THERAPEUTIC

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.

亨廷顿氏病（HD）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微妙问题，其次是缺乏协调和步态不稳。随着疾病的进展，身体的不稳定动作变得更加明显，沿着出现智力下降、行为和精神问题。受影响的个体也遭受渐进性体重减轻和肌肉萎缩。这种疾病通常会持续几十年，直到死亡。有一些有效的治疗一些症状，但没有治愈将停止或减缓疾病的进展。HD的遗传性意味着受影响个体的子女有50%的机会自己发展这种疾病。这种疾病是由编码亨廷顿蛋白（HTT）的单个基因突变引起的。该基因的突变版本和正常版本之间的唯一区别是接近其开始的DNA序列CAG的重复数量增加。这会导致HTT蛋白中谷氨酰胺（一种氨基酸，蛋白质的构建块）数量的增加，从而导致HTT蛋白在产生它的细胞中以异常的方式表现。犬尿氨酸途径（一种关键的代谢途径）的紊乱长期以来一直与HD症状的发展有关。该途径中的中心控制点是犬尿氨酸3-单氧酶（KMO）。事实上，如果KMO的活性被药物或遗传学抑制，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，可用的KMO抑制药物不能进入大脑-或显示有限的渗透率-这最终可能对临床测试很重要。此外，KMO抑制对大脑及其功能的影响尚不清楚，需要探索。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。这些将使我们能够确定是否在大脑中与血液中对KMO进行“遗传抑制”可以改善小鼠的HD症状，以及是否有一种方法可以产生更有效的保护作用。我们还将探索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改变。总之，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，最终将促进未来的临床试验。

项目成果

Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington's disease.

• DOI: 10.1038/s41598-021-84858-7
• 发表时间: 2021-03-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bondulich MK;Fan Y;Song Y;Giorgini F;Bates GP
• 通讯作者: Bates GP

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

• DOI: 10.1111/jnc.15360
• 发表时间: 2021-07
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Rodrigues FB;Byrne LM;Lowe AJ;Tortelli R;Heins M;Flik G;Johnson EB;De Vita E;Scahill RI;Giorgini F;Wild EJ
• 通讯作者: Wild EJ

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.

• DOI: 10.1016/j.biopsych.2016.12.011
• 发表时间: 2017-11-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Erhardt S;Pocivavsek A;Repici M;Liu XC;Imbeault S;Maddison DC;Thomas MAR;Smalley JL;Larsson MK;Muchowski PJ;Giorgini F;Schwarcz R
• 通讯作者: Schwarcz R

Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.

• DOI: 10.1371/journal.pbio.2003611
• 发表时间: 2018-04
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Robinson SW;Bourgognon JM;Spiers JG;Breda C;Campesan S;Butcher A;Mallucci GR;Dinsdale D;Morone N;Mistry R;Smith TM;Guerra-Martin M;Challiss RAJ;Giorgini F;Steinert JR
• 通讯作者: Steinert JR

Assessing and Modulating Kynurenine Pathway Dynamics in Huntington's Disease: Focus on Kynurenine 3-Monooxygenase.

评估和调节亨廷顿病的犬尿氨酸通路动力学：关注犬尿氨酸 3-单加氧酶。

• DOI: 10.1007/978-1-4939-7825-0_18
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sathyasaikumar KV