Generation of humanized mouse models to support therapeutic development for SYNGAP1 and STXBP1 disorders

Abstract

AbstractHeterozygous variants inSYNGAP1andSTXBP1lead to distinct neurodevelopmental disorders caused by haploinsufficient levels of post-synaptic SYNGAP1 and pre-synaptic STXBP1, which are critical for normal synaptic function. While several gene-targeted therapeutic approaches have proven efficaciousin vitro, these often target regions of the human gene that are not conserved in rodents, hindering the pre-clinical development of these compounds and their transition to the clinic. To overcome this limitation, here we generate and characterizeSyngap1andStxbp1humanized mouse models in which we replaced the mouseSyngap1andStxbp1gene, respectively, with the human counterpart, including regulatory and non-coding regions. Fully humanizedSyngap1mice present normal viability and can be successfully crossed with currently availableSyngap1haploinsufficiency mouse models to generateSyngap1humanized haploinsufficient mice.Stxbp1mice were successfully humanized, yet exhibit impaired viability (particularly males) and reduced STXBP1 protein abundance. Mouse viability could be improved by outcrossing this model to other mouse strains, whileStxbp1humanized females and hybrid mice can be used to evaluate target engagement of human-specific therapeutics. Overall, these humanized mouse models represent a broadly available tool to further pre-clinical therapeutic development for SYNGAP1 and STXBP1 disorders.