Journal Article

Validating therapeutic targets through human genetics

Plenge, Robert M., Scolnick, Edward M., Altshuler, David

2013

Overview

Key Points Existing preclinical models have a limited ability to test 'therapeutic hypotheses'; that is, whether perturbing a target in a given manner would benefit patients and have minimal toxicity. 'Experiments of nature', including human genetics, provide an estimate of dose–response curves at the time of target validation. There is an increasing number of studies in the literature demonstrating that genes with a series of disease-associated alleles represent promising drug targets. Here, we provide objective criteria to help prioritize research on the most promising targets and ultimately nominate a gene product as the target for a drug development programme. We highlight important limitations of human genetics in target validation, including a commentary on the genetic architecture of common diseases. We also discuss the role of genome-wide association studies (GWASs) and large-scale sequencing projects in drug discovery, emphasizing the importance of precompetitive collaborations that make clinical and genetic data available in a responsible manner. Many clinical trial failures can be traced back to the limited predictive value of preclinical models of disease. Plenge and colleagues discuss how knowledge from human genetics, such as naturally occurring mutations in humans that affect the activity of particular proteins, can be used as a tool to more effectively prioritize molecular targets in drug development. More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' — naturally occurring mutations in humans that affect the activity of a particular protein target or targets — can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose–response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug–gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/556 / 631/208 / Biomarkers / Biomedicine / Biotechnology / Cancer Research / Clinical trials / Clinical Trials as Topic / Dose-response relationship (Biochemistry) / Drug Discovery - economics / Drug Discovery - methods / Drug Discovery - standards / Drug targeting / Drugs, Investigational - adverse effects / Drugs, Investigational - pharmacokinetics / Drugs, Investigational - pharmacology / Drugs, Investigational - therapeutic use / Early Termination of Clinical Trials / Genetic aspects / Genetics, Medical / Humans / Medicinal Chemistry / Models, Biological / Molecular Medicine / Molecular Targeted Therapy / Pharmacogenetics / Pharmacogenetics - methods / Pharmacology/Toxicology / review-article / Treatment Failure