Figure 1

Outside-in and inside-out approaches to drug discovery for genetic diseases. (A) Outside-in screens start with a small-molecule screen vs. a model organism model of the genetic disease, followed by target identification (ID), validation, building an expanded library of small molecules based on structure activity relationships (SAR), and declaring a candidate drug for in vitro/in vivo pharmacokinetics (pharm)/absorption/distribution/metabolism/excretion (ADME)/ toxicology (tox) studies subsequent to a first-in-human trial. (B) Inside-out screens start with inhibition (normally) of a drug target being hypothesized to be able to ameliorate the genetic disease under study, followed by target validation in model organisms, a high-throughput screen for small molecules that inhibit the drug target, building an expanded library of small molecules based on SAR, determining the efficacy of lead compounds in model organisms, declaration of a candidate drug for in vivo pharm/ADME/tox, and a subsequent first-in-human trial. For both approaches, if the drug screen results in a known drug being identified that has efficacy in a model organism mimic of the genetic disease, then studies may be able to proceed directly to a first-in-human trial for disease treatment.