Kabuki Syndrome (KS) is a congenital multisystemic disorder hallmarked by distinctive facial features, short stature, intellectual disability, recurrent infection/hearing impairment and organ malformations. Patients require complex clinical management, and treatment options are limited. Human genetics studies have illuminated the pathobiology of KS, with mutations in two methyltransferases, KMT2D and KDM6A, accounting for ~80% of the disorder. Moreover, a mouse model for KMT2D, the most commonly-mutated KS gene, recapitulates craniofacial defects and key neuroanatomical and neurocognitive pathologies. However, a conundrum has persisted, in that the phenotype specificity of the KS pathology is challenging to reconcile with the ubiquitous functionality of KMT2D. Recently, we showed that mutations in RAP1A and RAP1B, two modulators of MEK/ERK signaling, are also mutated in KS and that at least one of the functions of KMT2D is to regulate the expression of RAP1B. Both transient and stable zebrafish models of RAP1A/B recapitulate key aspects of KS and showed persistent activation of RAS/MAPK signaling. Excitingly, both craniofacial and neurodevelopmental phenotypes genes could be rescued in vivo by attenuating RAS/MAPK signaling genetically. These data raised the possibility that RAS/MAPK inhibitors might be of therapeutic value, especially for the neurological deficits of KS that represent a credible postnatal intervention. For this purpose, we screened a collection of 50 BRAF/MEK/ERK inhibitors in a zebrafish model of KS, that included both known (and accessible) clinical assets and tool compounds. We identified three compounds, a BRAF inhibitor, an ERK inhibitor and a MEK inhibitor that could ameliorate the both micrognathia and neurogenesis in zebrafish. Importantly, neither small molecule had any toxic side-effects when tested through a rigorous, FDA-compliant toxicology paradigm. Here, we focus on two major postnatal traits in KS pathogenesis, intellectual disability and immunodeficiency, and propose to take these leads forward with a goal of developing clinical trials in KS patients. We have two Aims. First, we will establish how and when aberrant RAS/MAPK activation is associated with neurological deficits and immunodeficiency in an existing Kmt2d mouse model. Second, we will ask whether postnatal treatment of each compound at three timepoints (neonatal, juvenile, young adult) can ameliorate neuroanatomical, behavioral and immunological deficits. Together, these studies will form the foundation of an IND package and the design of eventual clinical trials with credible, rational endpoints.

Public Health Relevance

Kabuki syndrome (KS) is multisystemic disorder bereft of treatment options. Our prior studies have identified three RAS/MAPK inhibitors that can rescue key pathologies in a zebrafish KS model. Here, we 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 model. Successful completion of this proposal will lay a robust foundation for the development of a clinical asset for KS and will guide future clinical trials.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Tsilou, Katerina
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Rescindo Therapeutics, Inc.
United States
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