Kabuki Syndrome Mouse Model –Kmt2d Mouse ModelÂ
The Kmt2d mouse model represents a well-characterized, translationally relevant preclinical model for evaluating novel Kabuki Syndrome therapeutics, including epigenetic approaches Â
Kmt2d Mouse Model of Kabuki Syndrome Type 1
The Kmt2d+/βGeo mouse model represents a translationally relevant preclinical research model for evaluating novel therapeutics for Kabuki syndrome, a rare, neurodevelopmental, autosomal dominant disorder. Previously characterized by the laboratory of Dr Hans Bjornsson and colleagues, the Kmt2d+/βGeo mouse model shows consistent phenotypes both functionally and structurally (Bjornsson et al., 2014). Â
Developed to model a common pathogenic mechanism observed in the majority of cases of Kabuki syndrome type 1, the Kmt2d+/βGeo mouse model is a knock-in model carrying an expression cassette encoding a β-galactosidase neomycin resistance fusion protein (β-Geo) inserted into the Kmt2d (Mll2) locus on mouse chromosome 15. As heterozygous mutants in the Kmt2d gene, Kmt2d+/βGeo mice genetically model the loss-of-function mutations found in many Kabuki syndrome patients. Accordingly, the KMT2D proteins generated from this model lack functional methyltransferase activity, resulting in a genome-wide reduction in H3K4 trimethylation (H3K4me3); an epigenetic hallmark also observed in Kabuki syndrome. Disruption of H3K4me3 is particularly evident in the dentate gyrus of the hippocampus, leading to impaired neurogenesis and associated memory deficits. Phenotypically, the Kmt2d mouse model exhibits multiple features characteristic of Kabuki syndrome, including sensorineural hearing loss, flattened facial profile, craniofacial abnormalities, hippocampal memory deficits, and learning impairments. Â
✓ Under a collaboration with Kabuki Syndrome Foundation, InnoSer offers preclinical research services in the Kmt2d+/βGeo mouse modelÂ
✓ Kmt2d+/βGeo mice are actively bred at InnoSer, supporting not only quick study initiation times but also prophylactic treatment dosing schedulesÂ
✓ InnoSer offers validated behavioural battery assay to assess the effect of therapeutics on memory formation and learning performance
✓ InnoSer offers comprehensive preclinical support, including biodistribution studies, PK/PD profiling, early-stage toxicology, tolerability, and therapeutic efficacy assessmentsÂ
As a trusted preclinical contract research organization (CRO) specializing in rare neurological disorders, among others, InnoSer provides comprehensive end-to-end support for drug discovery and development. Together with the support from the Kabuki Syndrome Foundation (KSF), the nonprofit driving treatment development for Kabuki syndrome, InnoSer offers preclinical research services in the Kmt2d+/βGeo mouse model. This collaboration empowers leading biotech and pharmaceutical companies to develop effective treatments for Kabuki syndrome and other rare neurological diseases, addressing critical unmet medical needs. Â
Take advantage of InnoSer’s expertise, flexibility, and collaborative approach for your research. We support you in identifying new drug candidates, characterizing their pharmacological properties, and conducting rigorous safety and efficacy studies with state-of-the-art behavioral, bioanalytical, and histopathological readouts.Â
Kmt2d Mouse Model Readouts
Additional analyses
Biomarker analyses and/or post-mortem analyses:
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- Sensorineural hearing loss
- Weight assessment (growth retardation) Â
- Blood collection for blood/plasma analyses for PK/PD and biomarker analyses (i.e., ELISA for IgA levels), early-stage toxicology Â
- Terminal blood sampling, CSF, and organ collection for biochemical (i.e., DNA methylation and ChIP-seq histone profiles) and histopathological analyses (i.e., neurogenesis assessment in hippocampus) Â
- Bioluminescence biodistribution can be performed to follow up compound distribution in vivoÂ
The People Behind Your Research
Kabuki Syndrome Foundation
The Kmt2d mouse model is available at InnoSer via collaboration with the Kabuki Syndrome Foundation (KSF). KSF collaborates with a global network of leading clinicians, researchers, and patient advocates to drive high-impact, patient-centered research. Guided by its Medical and Scientific Advisory Board, KSF identifies critical gaps in knowledge, funds targeted research, and brings together experts to move science to treatments for the Kabuki syndrome community.Â
Frequently Asked Questions
How can researchers access the Kabuki Syndrome mouse model?
When do phenotypes emerge in the Kmt2d mouse model of Kabuki syndrome?
Phenotypes typically become evident from 10 weeks of age, making this a reliable time point for assessing therapeutic interventions (Zhang et al., 2021). We recommend getting in touch with our scientific team to discuss the specifics of your study, including the most appropriate age to start, dosing schedules, and recommended readouts, as these may depend on your therapeutic treatment strategy as well as your therapeutic target’s mechanism of action (MoA), among others. Contact us now.Â
Has the Kmt2d mouse model of Kabuki syndrome shown responsiveness to potential therapies?
Yes, the Kabuki Syndrome phenotype in this model has been shown to respond to postnatal treatment with agents that favor chromatin opening, such as HDAC inhibitors or the endogenous HDAC inhibitor-like ketone body β-hydroxybutyrate, highlighting its value for early-stage epigenetic drug development (Bjornsson et al., 2014).Â
Lysine-specific histone demethylase 1A (LSD1) removes H3K4 methyl marks introduced by KMT2D (Shi et al., 2004) and has therefore been hypothesized to mitigate the molecular and phenotypic impairments resulting from KMT2D loss of function (Cao et al., 2018). Previous research has demonstrated that treatment with an LSD1 inhibitor rescued defects in adult neurogenesis, restored proper gene expression, and rectified the genome-wide deficiency of specific histone methylation (Zhang et al., 2021). Â
Are there published examples of therapeutic efficacy in the Kmt2d mouse model of Kabuki syndrome?
Treatment with an LSD1 inhibitor led to normalization of memory and visuospatial learning deficits in Kmt2d+/βGeo mice, demonstrating the model’s utility in evaluating epigenetic therapies (Zhang et al., 2021).Â
Currently, vafidemstat, a clinical-stage LSD1 inhibitor developed by Oryzon Genomics, a biopharmaceutical company focused on the development of epigenetic-based drugs for CNS diseases and oncology, is being tested in the Kmt2d mouse model by InnoSer under a collaboration established between Kabuki Syndrome Foundation and Oryzon Genomics.
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AAALAC Accreditation
InnoSer has earned the AAALAC accreditation, demonstrating our commitment to responsible animal care and use. AAALAC International is a nonprofit organization that promotes the humane treatment of animals in science through voluntary accreditation and assessment programs. Our accreditation is valid for three years, incl. 2023. Read more about the AAALAC accreditation programme here.
Animal Welfare
The 3Rs impact everything from policy and regulatory change to the development and uptake of new technologies and approaches. This is why InnoSer has ongoing commitment and monitoring of these processes. The steps we practice maximize our ability to replace, reduce and refine animal involvement and facilitate our commitment to these principles when it comes to research and drug development.
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