Abstract
Heterozygous variants in SYNGAP1 and STXBP1 lead 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 efficacious in 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 characterize Syngap1 and Stxbp1 humanized mouse models in which we replaced the mouse Syngap1 and Stxbp1 gene, respectively, with the human counterpart, including regulatory and non-coding regions. Fully humanized Syngap1 mice present normal viability and can be successfully crossed with currently available Syngap1 haploinsufficiency mouse models to generate Syngap1 humanized haploinsufficient mice. Stxbp1 mice 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, while Stxbp1 humanized 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.
Competing Interest Statement
Benjamin L. Prosser and Beverly L. Davidson are inventors on two patents relevant to therapeutic development for neurodevelopmental disorders, PCT/US2020/031672 and UPN-22-9943. Alex J. Felix is an inventor on UPN-22-9943.
Footnotes
Author emails: Alex J. Felix: Alejandro.JimenezFelix{at}Pennmedicine.upenn.edu
Taryn Wilson: taryn.wilson{at}pennmedicine.upenn.edu
Rani Randell: rrani{at}sas.upenn.edu
Nicolas Marotta: nick.marotta{at}pennmedicine.upenn.edu
Keita Uchida: keita.uchida{at}pennmedicine.upenn.edu
Michael J. Boland: michael.boland{at}pennmedicine.upenn.edu
Beverly L. Davidson: davidsonbl{at}chop.edu
Funding information This work was supported by R21 NS118280 from NIH-NINDS to B.L.P. and B.L.D.
Conflicts of interest BLP and BLD are inventors on two patents relevant to therapeutic development for neurodevelopmental disorders, PCT/US2020/031672 and UPN-22-9943. AJF is an inventor on UPN-22-9943.
Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request.