Developing a new therapeutic agent for Kabuki syndrome

Kabuki SyndromeKSis a congenital multisystemic disorder hallmarked by distinctive facial featuresshort statureintellectual disabilityrecurrent infection hearing impairment and organ malformationsPatients require complex clinical managementand treatment options are limitedHuman genetics studies have illuminated the pathobiology of KSwith mutations in two methyltransferasesKMT D and KDM Aaccounting forof the disorderMoreovera mouse model for KMT Dthe most commonly mutated KS generecapitulates craniofacial defects and key neuroanatomical and neurocognitive pathologiesHowevera conundrum has persistedin that the phenotype specificity of the KS pathology is challenging to reconcile with the ubiquitous functionality of KMT DRecentlywe showed that mutations in RAP A and RAP Btwo modulators of MEK ERK signalingare also mutated in KS and that at least one of the functions of KMT D is to regulate the expression of RAP BBoth transient and stable zebrafish models of RAP A B recapitulate key aspects of KS and showed persistent activation of RAS MAPK signalingExcitinglyboth craniofacial and neurodevelopmental phenotypes genes could be rescued in vivo by attenuating RAS MAPK signaling geneticallyThese data raised the possibility that RAS MAPK inhibitors might be of therapeutic valueespecially for the neurological deficits of KS that represent a credible postnatal interventionFor this purposewe screened a collection ofBRAF MEK ERK inhibitors in a zebrafish model of KSthat included both knownand accessibleclinical assets and tool compoundsWe identified three compoundsa BRAF inhibitoran ERK inhibitor and a MEK inhibitor that could ameliorate the both micrognathia and neurogenesis in zebrafishImportantlyneither small molecule had any toxic side effects when tested through a rigorousFDA compliant toxicology paradigmHerewe focus on two major postnatal traits in KS pathogenesisintellectual disability and immunodeficiencyand propose to take these leads forward with a goal of developing clinical trials in KS patientsWe have two AimsFirstwe will establish how and when aberrant RAS MAPK activation is associated with neurological deficits and immunodeficiency in an existing Kmt d mouse modelSecondwe will ask whether postnatal treatment of each compound at three timepointsneonataljuvenileyoung adultcan ameliorate neuroanatomicalbehavioral and immunological deficitsTogetherthese studies will form the foundation of an IND package and the design of eventual clinical trials with crediblerational endpoints Kabuki syndromeKSis multisystemic disorder bereft of treatment optionsOur prior studies have identified three RAS MAPK inhibitors that can rescue key pathologies in a zebrafish KS modelHerewe aim to investigate the roles of RAS MAPK pathway during KS pathogenesis and test the efficacy and safety of these compounds in a mouse KS modelSuccessful completion of this proposal will lay a robust foundation for the development of a clinical asset for KS and will guide future clinical trials