Adenosine A2A receptor cross-activation of TrkB in Huntington's disease

描述(申请人提供)：亨廷顿病(HD)是一种显性遗传性疾病，由亨廷顿蛋白基因(HTT)中的多谷氨酰胺结构域扩张引起，仅在美国就有约35,000人受到影响。HTT的正常功能在很大程度上仍不清楚，其发病机制(S)涉及突变蛋白的假定功能获得以及潜在的功能丧失/与正常HTT等位基因的干扰。关键的是，缺乏临床验证的HD靶点，迫切需要识别和了解潜在有益药物靶点的作用机制，重要的是，需要证明这些靶点可以使用具有良好的类药物特性的治疗候选分子来解决。目前的建议集中在两个这样的候选靶点/通路之间的潜在交集，这两个候选靶点/通路越来越多地与HD有关：腺苷2A受体(A2AR)和TrkB受体。最近的证据表明，A2AR下游信号的重要方面实际上可能是通过其交叉激活TrkB受体而介导的，这种方式独立于TrkB配体，如BDNF，其正常的纹状体供应在HD发病过程中受到损害。如果是这样的话，这种机制，如果在HD的背景下运作，可能提供一个治疗机会，利用A2AR配体通过TrkB的交叉激活为退化的纹状体神经元提供营养支持。此外，如果这一机制得到支持，晚期临床测试中的BBB穿透性A2AR配体已经可以用于HD模型的评估，以潜在地重新用于临床治疗HD。因此，R21建议的目的是为核心假设提供原则证明，即A2AR调节可以通过交叉激活TrkB受体而有利于在HD背景下经历神经变性的纹状体神经元。对于这些研究，我们将使用基于脑切片的HD分析模型，关键是保留纹状体和皮质的局部组织环境，以便最大限度地预测体内环境，同时提供体外/体外准备的实验通道。如果支持，基于脑切片的HD测试中的这些发现应该为R01的全面应用提供必要的基础，以使用神经行为和神经病理结果测量在全动物HD模型中检查这一机制和治疗机会。 公共卫生意义：亨廷顿病(HD)是一种致命的显性遗传病，由亨廷顿蛋白基因(HTT)中的多谷氨酰胺结构域扩张引起，仅在美国就有约3.5万人受到影响。目前，对于这种毁灭性的疾病还没有已知的治疗方法，现有的姑息治疗在治疗HD过程中出现的神经精神症状和运动障碍方面只有部分有效。缺乏HD的临床验证靶点，迫切需要识别和了解潜在有益药物靶点的作用机制，重要的是，需要证明这些靶点可以使用具有良好的类药物特性的治疗候选分子来解决。目前的提案将测试现有的靶向腺苷2A受体的小分子药物可以用来进入一条“神经营养”或健康维持途径，即BDNF-TrkB途径，该途径缺乏HD，并导致大脑重要部分，特别是纹状体的退化。到目前为止，BDNF蛋白本身的使用已被证明在临床试验中存在很大问题，因此通过替代方法激活其受体TrkB提供了一个潜在的终点，通过该终点，具有更好药理性能的候选药物可以用于为HD受损的纹状体提供关键的神经营养支持。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a dominant genetic disorder arising from expansions of the polyglutamine domain in the huntingtin gene (htt), affecting some 35,000 people in the US alone. The normal functions of htt remain largely unknown, with disease mechanism(s) involving presumptive gains-of-function from the mutant protein as well as potential loss of function/interference with the normal htt allele. Critically, the lack of clinically validated targets for HD places an urgent need on identifying and understanding the mechanisms of action of potentially beneficial drug targets, and, importantly, on demonstrating that such targets can be addressed using therapeutic candidate molecules with good, drug-like properties. The present proposal focuses on the potential intersection between two such candidate targets/pathways that have increasingly been implicated in HD: the adenosine 2A receptor (A2AR) and the TrkB receptor. Recent evidence suggests that significant aspects of A2AR downstream signaling may actually be mediated through its cross-activation of the TrkB receptor in a manner that is independent of TrkB ligands such as BDNF, whose normal provision to the striatum by the cortex is compromised during HD pathogenesis. If so, such a mechanism, if operant in the context of HD, could present a therapeutic opportunity to use A2AR ligands to provide trophic support to degenerating striatal neurons via their cross-activation of TrkB. Moreover, if this mechanism is supported, BBB-penetrant A2AR ligands in late-stage clinical testing are already available for evaluation in HD models for potential repurposing for clinical use in treating HD. Thus, the goal of this R21 proposal is to provide proof-of-principle for the core hypothesis that A2AR modulation can provide benefit to striatal neurons undergoing neurodegeneration in the context of HD through cross-activation of the TrkB receptor. For these studies, we will use a brain slice-based assay model for HD that, critically, retains the local tissue environment of the striatum and cortex in order to be maximally predictive for the in vivo setting while providing the experimental access of an in vitro/ex vivo preparation. If supportive, these findings in a brain slice-based HD assay should provide the necessary foundation for a full R01 application to examine this mechanism and therapeutic opportunity in whole-animal models of HD using both neurobehavioral as well as neuropathological outcome measures. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a fatal, dominant genetic disorder arising from expansions of the polyglutamine domain in the huntingtin gene (htt), affecting some 35,000 people in the US alone. Currently, no cures are known for this devastating disease, with palliative treatments available that are only partially effective in treating the neuropsychiatric symptoms and motor disabilities that develop over the course of HD. This lack of clinically validated targets for HD places an urgent need on identifying and understanding the mechanisms of action of potentially beneficial drug targets, and, importantly, on demonstrating that such targets can be addressed using therapeutic candidate molecules with good, drug-like properties. The present proposal will test the proposition that existing small molecule drugs targeting the adenosine 2A receptor could be used to tap into a "neurotrophic" or health-sustaining pathway, the BDNF-TrkB pathway, that becomes deficient in HD and contributes to the degeneration of vital parts of the brain, notably the striatum. To date, the use of the BDNF protein itself has proven to be highly problematic in clinical trials, so activation of its receptor, TrkB, by alternative means provides a potential end run by which drug candidates with much better pharmaceutical properties could be used to supply the critical neurotrophic support to the striatum that is compromised in HD.