Target Validation for Huntington’s Disease

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.