Columbia University

Technology Ventures

Genetic Pharmacotherapy for Target Validation in Neuropsychiatric Disorders

Technology #2931

“Lead Inventor: Stephen Rayport M.D./Ph.D.

Neuropsychiatric Disorders Require Tools to Test Relevance of Drug Targets
Drug discovery for neuropsychiatric disorders is a time and resource intensive process. Traditionally, molecules are screened and further modified by synthetic chemistry to generate high affinity drugs that target proteins of interest. However, only after the generation of these compounds does the therapeutic potential of targeting this protein become apparent. While this methodology has proven to be successful historically, there are many cases of rational drug design that mediate no therapeutic benefit. Furthermore, even when educated guesses are made based on scientific literature, they do not guarantee that targeting any particular protein would have clinical benefits. There is currently a lack of tools available to test the in vivo relevance of drug targets prior to the development of drug antagonists.

Genetic Tools Validate Drug Targets of Interest in Mouse Models This technology would provide the necessary tools to validate drug targets of interest in mouse models of neuropsychiatric disorders prior to their development. This technology utilizes mouse lines that can temporally and spatially reduce protein expression. The reduction demonstrated by this system is comparable to the levels of reduction seen when treating with high affinity drugs in vivo. Mouse lines are genetically engineered to contain genes of interest that are flanked by recognition sites of a recombinase. This recombinase can remove the intervening coding region, and as a result delete this gene from the genome. This recombinase can be put under the control of tissue specific promoters, in this case the brain, and further be regulated by pharmacological means to temporally activate the recombinase. These genetic tools can be combined with other mouse models of neuropsychiatric disorders to assess whether the reduction in protein function has the potential to alleviate systems or has unpredicted deleterious effects on brain biology.

Applications: • Validation of drug targets prior to the development of high affinity antagonists. • Analyze the in vivo efficacy of target genes in mammalian whole animal system. • Test currently existing drugs for specificity. • Determine if the drug target of interest has unpredicted functions that might render this drug target undesirable in terms of clinical safety.

Advantages: • Applicable to any protein of interest, even essential genes due to temporal and spatial regulation of excision. • More than one drug target of interest can be modulated at once, which may mimic current neuropsychiatric drugs that have low affinity off target effects for multiple receptors. • Once the target is validated, the system can be used to test specificity of developed compounds. • Can be applied to other diseases in addition to neuropsychiatric disorders. • Mouse lines are readily available that contain alleles flanked by the recombinase sequence. • In contrast to traditional conditional knockout mice, this system pharmacologically controls the recombination process for enhanced temporal control.

Patent Status: Copyright

Licensing Status: Available for Licensing and Sponsored Research Support ”