Year: 2011
Type: book-chapter
Abstract: IntroductionIn current drug development, proof-of-concept-determining whether a ligand engaging its target is likely to be therapeutic-requires specific ligands.This presents a catch-22, as the motivation to develop ligands requires proof-of-concept studies that cannot be conducted without ligands.A strategy we term genetic pharmacotherapy-a refinement of genetic blockade focused on druggable targets-obviates the catch-22 by enabling proof-of-concept studies prior to the development of specific ligands via genetic means in mouse models.In this strategy, which could help avert investment in molecular entities that will ultimately prove therapeutically inefficacious, a gene is conditionally down-regulated via a molecular switch in adult mice.Both the precise temporal control of the intervention and the consequent change in target protein function parallel the administration of drugs, with the additional advantage of perfect specificity.Moreover genetic pharmacotherapy overcomes the impediment of the blood-brain barrier, which makes developing ligands for psychiatric disorders particularly challenging.Here, we describe the transgenic technologies that form the basis for the strategy, discuss the advantages and limitations in juxtaposition with other gene expression modification approaches, contrast examples of prior implementation, address the feasibility for systematic use, and illustrate past and future opportunities.Although the molecular tools are widely available, genetic pharmacotherapy has only been implemented outside the central nervous system (CNS), despite its particular utility for CNS disorders.The systematic application of this strategy should foster the development of new, innovative molecular therapies. The conceptual basis and requisite components of genetic pharmacotherapyWe define genetic pharmacotherapy as the use of a genetic intervention to achieve a pharmacological effect.Genetic pharmacotherapy has two requirements.First, genetic blockade must be universal -reaching all cells in the body, including the brain -to simulate organism-wide drug distribution.Second, induction of gene-modulation must be temporally controllable, as opposed to originating during embryogenesis, so that target modulation occurs as it would with drug administration.While traditional knockout
Source: InTech eBooks
DOI: 10.5772/29478
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4213098837