Epigenetic therapy in autoimmunity An idea by Theodoros Savvidis

What is epigenetic therapy? “Epigenetic therapy is the use of drugs or other epigenome-influencing techniques to treat medical conditions. “ Many diseases including cancer, heart diseases, diabetes and mental illnesses are influenced by epigenetic mechanisms, and epigenetic therapy offers a potential way to influence those pathways directly.”

Epigenetic Therapies Agents DNA-methyltransferases Inhibitors HATs and HDACs Inhibitors HMTs and HDMs Inhibitors miRNA biomarkers and interventions Inhibitors of other pathways (e.g. JAK-STAT)

Diseases known to have an epigenetic factor Cancer Type I Diabetes (Diabetic Retinopathy) Cardiac Disfunction Fear, Anxiety and Trauma Schizophrenia Etc…

Epigenetic drugs approved by FDA Epi-drugs For example, high levels of sulphoraphane, an HDACi naturally found in broccoli sprouts has been associated with H3 and H4 hyperacetylation Byrne et al. 2014

Two mechanisms of action of epi-drugs Cherblanc et al. 2013

More Epigenetic Drugs in Trials FDA approved! Boumber & Issa 2011

Autoimmune Diseases More than 80 disorders described Affecting ~7% of the population Interplay between genetics and environment Discordance of diseases between monozygotic tweens!

Epigenetics in Autoimmunity Role of Th cells in autoimmunity Role of the balance between the plastic lineages Th17 and Tregs Reactivation of Tregs = good strategy against autoimmunity (HDAC9i against IBD, Mottet et al. 2003) Treating Treg cells from psoriasis patients with HDAC inhibitor TSA showed prevented the Th17-like phenotype

Epigenetics in Autoimmunity Type I Diabetes Rheumatoid Arthritis System Lupus Erythematosus Multiple Sclerosis Inflammatory Bowel Disease (e.g. Crohn’s Disease and Ulcerative Colitis) Asthma A microarray study by Miao et al. established the presence of an aberrant histone methylation profile in lymphocytes of T1D patients Exposure to diesel exhaust particles (DEP) has been shown to change the overall DNA methylation profile in healthy elderly people

Epigenetics in Autoimmunity Specific examples: HDACi’s in mouse models

Limitations Not all inhibitors are the same! Specificity of the epi-drugs… Not so effective in the forms of autoimmunity caused also by genetic factors (huge variety of targets both histone and non-histone for e.g. HDMT and HDACs)

Why now? Razvi and Oosta (2016)

Why now? National Institute of Health, Roadmap project in the US European Union initiated Human Epigenome Project (HEP) New Next Generation Sequencing technologies HEP also focusing on environmental agents affecting gene expression… Systematic, large scale epigenome projects such as the National Institute of Health Roadmap project in the US or the European Union initiated Human Epigenome Project (HEP) with the latter focusing on different cell types found in human blood will provide new insights into the epigenetic mechanisms.

Thank you!