Poster Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

Targeting KDM6A as a novel therapeutic strategy for treating craniosynostosis in children with Saethre-Chotzen syndrome (#101)

Clara Pribadi 1 2 , Esther Camp-Dotlic 1 2 , Dimitrios Cakouros 1 2 , Peter Anderson 2 3 , Stan Gronthos 1 2
  1. Mesenchymal Stem Cells Laboratory, Adelaide Medical School, Faculty of Health & Medical Sciences , University of Adelaide , Adelaide, SA, Australia
  2. South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
  3. Australian Craniofacial Unit , Women's and Children's Hospital, North Adelaide, South Australia, Australia

The upper part of the mammalian skull (calvaria) is made up by five flat bones which are separated by open sutures during childhood. Craniosynostosis is a condition where calvarial sutures fuse prematurely, as a result of aberrant osteogenic differentiation of calvarial mesenchymal stromal cells on the suture sites. Saethre-Chotzen Syndrome (SCS) is one of the most common forms of craniosynostosis (occurring in ~1/25,000 births), which is caused by a loss-of-function mutation of TWIST-1 gene. This condition could lead to skeletal deformities and neurological deficits. Currently, the only treatment for craniosynostosis involves the removal of the affected sutures and remodelling of the skull, which could lead to serious complications. Thus, an attempt to identify a novel drug therapy that eliminates the use of invasive surgery is paramount.

This project utilised the established SCS mouse model, Twist-1del/+ heterozygous mutant mice, to investigate this condition further. The results show that the expression of an epigenetic enzyme, called KDM6A, is negatively regulated by TWIST-1 and is upregulated in SCS mouse model, compared to wild type control littermate mice. KDM6A has been shown previously by our laboratory to promote osteogenesis in bone marrow-derived mesenchymal stromal cells. This suggests that KDM6A could be a potential target to treat the aberrant osteogenesis seen in SCS patients. Thus, this study aims to determine the effectiveness of a pharmacological inhibitor of KDM6A, GSK-J4, in alleviating the aberrant increase of osteogenic differentiation in calvarial stromal cells and explants-derived from SCS mouse model.

The results demonstrate for the first time that GSK-J4 could inhibit the osteogenic potential of SCS mouse calvarial stromal cells and explants at concentrations up to 2μM with minimal toxic effects in vitro. Thus, GSK-J4 could be a potential therapeutic strategy for treating craniosynostosis in children with SCS. Further studies including analysis of the efficacy of GSK-J4 in Twist-1del/+ mice via local administration in vivo are required to assess GSK-J4 as a treatment for craniosynostosis in SCS.

 

  • Have you presented your abstract at another international meeting?: No