TITLE: A Ketogenic Diet Rescues Neurogenesis Defects in a Mouse Model of Kabuki Syndrome
CASE NUMBER: C13532
UNMET NEED
Kabuki syndrome (KS) is a rare genetic disease resulting in intellectual disability, seen in association with postnatal growth retardation, immunological dysfunction and characteristic facial features. Currently, there are two known genes, KMT2D and KDM6A, mutations in either of which can lead to KS. Each of these genes plays an independent role in the process of chromatin opening. If a deficiency of chromatin opening plays a role in the pathogenesis of the disease, agents that favor chromatin opening, such as the histone deacetylase inhibitors (HDACi), could ameliorate any ongoing disease processes. Previous work in the Bjornsson group has demonstrated the therapeutic potential of histone deacetylase inhibition for Kabuki syndrome and shown that a particular histone deacetylase inhibitor rescues many of the pathological phenotypes found in a mouse model of Kabuki syndrome, they hypothesized that beta-hydroxybutyrate (either induced through a ketogenic diet or exogenously administration) should have similar therapeutic effects.
PROBLEM SOLVED
JHU researchers have now demonstrated that in their mouse model of Kabuki syndrome rescue of multiple markers of the disease state after two weeks of the ketogenic diet with concomitant beta-hydroxybutyrate elevation, including rescue of the epigenetic abnormality (deficiency of H3K4me3 in neurons) and rescue of the neurogenesis abnormality in the granule cell layer of the dentate gyrus. Furthermore, there is also rescue of hippocampal memory defect previously found in this mouse model in a Morris water maze. They also have demonstrated rescue of the neurogenesis defect upon exogenous administration of beta-hydroxybutyrate which could be an additional therapeutic strategy for Kabuki syndrome and related disorders.
MAJOR RESULTS
1. First time that a nutritional intervention (the ketogenic diet) can rescue hippocampal memory defects and abnormalities of adult neurogenesis observed in a mouse model of Kabuki syndrome.
2. First time ketogenic diet has been used as a therapeutic strategy for Kabuki syndrome or other genetic intellectual disability disorders.
3. Rescue of the neurogenesis defect with direct injection of beta-hydroxybutyrate making that exogenous administration of beta-hydroxybutyrate another potential therapeutic strategy for this group of disorders.
DISEASE INDICATION
Kabuki Syndrome/Mendelian Disorder
ASSOCIATED PUBLICATIONS
- PMC4406328 -
TECHNOLOGY CLASSIFICATION
Primary Category: Therapeutics
Primary Subcategory: Therapeutic Method
ASSOCIATED REPORTS OF INVENTION (ROIs) AND INTELLECTUAL PROPERTY (IP) FILING NUMBERS
ROI #: C13532
TITLE: Compositions and methods for treating kabuki syndrome and related disorders
STATUS: PCT Pending
PRIORITY DATE: 5/30/2014
IP FILING NUMBERS: WO 2015184279 A1
