From Bench to Bedside
The session concluded with presentations on two abstracts from the conference. Chris M. Dunn, a master’s student at the University of Oklahoma Health Sciences Center, Oklahoma City, presented his research, titled, “Epigenetic Editing of FOXP3 in Human T Cells Is Sufficient to Induce Overexpression and Create a Regulatory T Cell Phenotype in Vitro.”
Mr. Dunn described the epigenetic editing of the transcription factor FOXP3 using a dCas9-TET1 construct. He acknowledged, “There is a hot debate on whether FOXP3 expression and CTLA4 expression are related in any way.” Nevertheless, his team was able to induce DNA demethylation, overexpression and a regulatory T cell phenotype.
“Our data are intriguing but need confirmation, particularly to clarify the persistence of induced DNA methylation changes and resistance to phenotype switching. If confirmed, this approach has the potential to significantly improve upon current methods of Treg [regulatory T cell] generation,” he explained.
Jieun Shin, PhD, with the Research Institute of Chong Kun Dang Pharmaceutical Corp., Yongin, Korea, presented her group’s research on CKD-506, a first-in-class selective and potent histone deacetylase (HDAC) 6 inhibitor. Dr. Shin reported data from ex vivo studies of RA patient samples, as well as data from the rat adjuvant-induced arthritis (AIA) model. She began her presentation by describing a macrophage cell line that overexpressed HDAC6 and had increased production of inflammatory cytokines. When she and her colleagues treated these cells with CKD-506, they were able to inhibit the inflammatory mediators and inhibit NF-kB and AP-1 signaling in the cells.
When the investigators treated RA patient samples with CKD-506, they were also able to inhibit inflammatory mediators, specifically TNF-α. In addition, CKD-506 induced IL-10 production when RA patient peripheral blood mononuclear cells were stimulated with lipopolysaccharide. When they looked at cellular function, they found CKD-506 induced CTLA4 and enhanced Treg activity in PBMCs from patients with RA. Specifically, CD4+CD25– cells differentiated into Treg cells in the presence of CKD-506. Dr. Shin and her colleagues then orally administered CKD-506 to AIA rats and found it not only repressed arthritis in the rats, but it also acted synergistically with methotrexate.
CKD-506 improved symptoms of RA via regulation of inflammation and T cell function, according to Dr. Shin. CKD-506 is currently in preparation for a phase 2a clinical trial in the European Union for the treatment of patients with moderate to severe RA. The team is also exploring the possibility CKD-506 will be effective in the treatment of inflammatory bowel disease.