Patient iPSC derived neural synaptic screen for drug discovery

DESCRIPTION provided by applicant We propose to Use a set of human schizophrenia SCZ disease models utilizing induced pluripotent stem cells iPSCs derived from SCZ patients to evaluate six advanced SCZ compounds from a pharma partner to assess their potential to be further developed into SCZ therapeutics and Discover new compound leads for SCZ We will use one of the models a validated synaptic density screen in well format using forebrain glutamatergic neurons FGNs derived from iPSCs bearing a Disrupted in schizophrenia DISC frameshift mutation We will characterize the hits in the additional SCZ iPSC models SCZ affects around of the worldandapos s population and is a major public health problem About of SCZ patients do not response to available medications only show partial response The industryandapos s hunt for better therapeutics have been thwarted by inadequacy of current drug discovery models Patient specific iPSC derived neurons hold great promises as effective disease models for mechanism studies and drug discovery Our team has generated and characterized SCZ iPSC lines from patients with different genetic risk factors and background These cell lines isogenic and normal controls will be utilized for this proposal We have optimized differentiation protocols that produce highly pure populations of cortical neural progenitors NPCs GABAergic interneurons and FGNs andgt andgt and andgt respectively The purity of differentiated populations allows us to confidently attribute assay readouts to intrinsic properties of the cellular models and experimental manipulations The high throughput synaptic screen is validated Correcting DISC mutation in patient iPSCs corrected the synaptic and other functional defects Introducing DISC mutation into normal iPSCs or mice recreated cellular deficits and created animal behavioral and cognitive deficits A mechanism relevant compound rescues deficits in both DISC FGNs and DISC mutant mice Nine other compounds mechanistically related to this compound was shown to rescue synaptic deficit in a separate targeted screen Aim Evaluate six advanced discovery development SCZ compounds from a pharma partner for potential continued development for SCZ We will differentiate SCZ and control iPSC lines into NPCs and then onto FGNs and GABAergic neurons Treat the neurons for weeks with the six compounds at four concentrations Assess treatment effects with synaptic screen and other morphological and functional assays Aim Conduct primary screen of compounds with synaptic screen and confirmation screens with additional SCZ iPSC models We will use synaptic density assay with one DISC line for primary screen We will use its isogenic control and another DISC line with different clinical presentation for counter and confirmation screens and further characterize with other SCZ lines to generate leads PUBLIC HEALTH RELEVANCE Schizophrenia affects of the population is challenging to treat and is one of the leading public health problems in the US and worldwide of Schizophrenia patients do not respond to treatment and another only partially respond Therapeutics that can treat negative symptoms are lacking JuvoBio Pharmaceuticals has develop innovative stem cell based assays and will use them to evaluate advance schizophrenia candidates as well as to discovery new compounds