Kwak Seung P., Wang James K. T., Howland David S.
During the past several decades, pharmaceutical safety and efficacy have improved considerably with the elucidation of mechanisms of drug action in the disease context and a better understanding of the desired drug target profiles. The ability to fine-tune the target profile of many drugs has led to the premise that the optimal basis for the development of a safe and effective drug is the targeting of a single gene product. In the “omics” era of biology, the ability to rapidly identify and characterize the “druggable genome” in its entirety has created the opportunity to broadly test the validity of this premise. However, the torrent of potential drug targets resulting from this approach presents a new set of challenges, particularly the development of a robust and efficient target validation process. Such a process must be capable of screening a sizeable number of putative targets and identifying the best candidates for the lengthy, uncertain, and expensive process of drug development. An effective target validation process depends on biological models or systems that exhibit the known properties of the disease and respond to intervention in a manner predictive of clinical outcome. Pre-existing benchmarks or “gold standard” treatments known to be effective in the clinic can be used to confirm the effectiveness of a target validation process by showing that the process is capable of “discovering” the benchmarks. The challenge is much greater for diseases without existing therapeutics. The absence of clinically successful benchmarks introduces significant uncertainty into all upstream drug discovery processes, as their validity cannot be confirmed. This is the difficult situation faced by therapeutic development for Huntington’s disease (HD) and arguably for all neurodegenerative diseases. This chapter will describe the approaches adopted by the CHDI Foundation—an organization that is dedicated to the singular mission of developing HD therapeutics—to manage these limitations while moving forward with HD drug discovery and development (see also Chapter 8, this volume). The chapter is divided into four sections. In the first section, we briefly review the challenges inherent in target validation for HD. In the second, we present our current target validation processes and their deployment for the existing list of potential targets. In the third, we discuss the operational bottlenecks and scientific challenges in the target validation process, as well as several methods for meeting these challenges. In the last section, we discuss our longer-term goal of developing new approaches to improve our current processes. The ultimate validity of our target validation processes can only be demonstrated by the development of an effective drug for HD.
在过去几十年间，随着在疾病背景下对药物作用机制的阐明以及对理想药物靶点特征的更好理解，药物的安全性和有效性有了显著提高。对许多药物的靶点特征进行微调的能力引发了这样一种前提，即开发安全有效药物的最佳基础是针对单一基因产物。在生物学的“组学”时代，能够快速全面地识别和表征“可成药基因组”创造了广泛检验这一前提有效性的机会。然而，这种方法产生的大量潜在药物靶点带来了一系列新挑战，尤其是开发强大而高效的靶点验证流程。这样一个流程必须能够筛选大量假定靶点，并为漫长、不确定且昂贵的药物开发过程确定最佳候选靶点。有效的靶点验证流程依赖于能够展现疾病已知特性并以预测临床结果的方式对干预做出反应的生物学模型或系统。已知在临床上有效的现有基准或“金标准”治疗方法可用于通过表明该流程能够“发现”这些基准来确认靶点验证流程的有效性。对于没有现有治疗方法的疾病，挑战要大得多。缺乏临床成功的基准给所有上游药物发现流程带来了重大不确定性，因为其有效性无法得到确认。这就是亨廷顿舞蹈病（HD）治疗开发所面临的困境，并且可以说所有神经退行性疾病都是如此。本章将描述CHDI基金会（一个致力于开发HD治疗方法这一独特使命的组织）为应对这些限制同时推进HD药物发现和开发所采用的方法（另见本书第8章）。本章分为四个部分。在第一部分，我们简要回顾HD靶点验证中固有的挑战。在第二部分，我们介绍我们当前的靶点验证流程及其在现有潜在靶点列表中的应用。在第三部分，我们讨论靶点验证流程中的操作瓶颈和科学挑战，以及应对这些挑战的几种方法。在最后一部分，我们讨论我们开发新方法以改进当前流程的长期目标。我们靶点验证流程的最终有效性只能通过开发出一种有效的HD药物来证明。
