A Clinical View on BET Inhibition in CKD & CVD: Understanding Recent Data and Future Perspectives Kam Kalantar-Zadeh, MD, MPH, PhD FACP, FAAP, FAHA, FASN, FNKF Twitter/FB: @KamKalantar Professor of Medicine, Pediatrics and Public Health Chief, Division of Nephrology and Hypertension University of California Irvine, School of Medicine Veteran Administrations’ Long Beach Healthcare System, Long Beach, CA Professor of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA International Steering Committee World Kidney Day (WKD) www.WorldKidneyDay.org Immediate Past President International Society of Renal Nutrition & Metabolism (ISRNM) www.RenalNutrition.com ISN Council Member International Society of Nephrology (ISN)
Faculty Disclosure: Prof. Kamyar Kalantar-Zadeh, MD, MPH, PhD Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current sponsor(s) YES NO Dr. K. Kalantar-Zadeh has received honoraria and/or support from Abbott, Abbvie, Alexion, Amgen, ASN (American Society of Nephrology), Astra-Zeneca, B From any institution YES NO Aveo, Chugai, DaVita, Fresenius, Genentech, Haymarket Media, Hofstra Medical II I have been a speaker or participant in accredited CME/CPD School, IFKF (International Federation of Kidney Foundations), ISH A From current sponsor(s) YES NO (International Society of Hemodialysis), International Society of Renal Nutrition B From any institution YES NO & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, III I have been a consultant/strategic advisor etc Kabi, Keryx, Novartis, OPKO, NIH (National Institutes of Health), NKF (National Kidney Foundations), Pfizer, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, A For current sponsor(s) YES NO Shire, Vifor, UpToDate, ZS-Pharma. B For any institution YES NO IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation YES NO B Not related to presentation YES NO
Unmet Need in Diabetes and CKD: Epigenetics and CVD Risk in CKD & Diabetes • Patients with diabetes and CKD have far greater risk of CVD death, MI, Stroke and Heart Failure, leading to shortened life span. • Diabetes and CKD patients have highly dysregulated genes and distorted gene expression and have many genes and proteins that drive CVD risk → Epigenetic Basis of CKD • Novel approaches to potentially reduce this high risk are urgently needed
Key DNA and histone epigenetic modifications. Impact on gene expression Histones: acetylation methylation crotonylation DNA: methylation Fontecha-Barriuso M et al. Nephrol Dial Transplant. 2018 Mar 9. doi: 10.1093/ndt/gfy009. [Epub ahead of print]
Therapeutic targeting of DNA and histone DNA: epigenetic modifications methylation in kidney injury Histones: acetylation BET proteins Epigenetic reader Histones: methylation Histones: crotonylation Fontecha-Barriuso M et al. Nephrol Dial Transplant. 2018 Mar 9. doi: 10.1093/ndt/gfy009. [Epub ahead of print]
Epigenetics modulation of distorted genes and gene expression, via novel molecular target Bromodomain and Extraterminal Domain ( BET) inhibition , has the potential to regulate key pathways and markers of high risk including calcification and inflammation in diabetes and CKD disease • The Epigenetic code refers to secondary modifications to chromatin components that regulate its activity • Transcription is regulated by addition, removal or recognition of these modifications (writers, erasers, readers) • Acetylation is associated with active transcriptional regions of chromatin • BET (Bromodomain and Extraterminal Domain) proteins bind to acetylated lysines on histones and recruit additional transcription factors 6
Mechanism of Action of Apabetalone BET proteins, such as BRD4, bind acetylated lysine (ac) on histones or transcription factors (TF) via bromodomains (BD), and recruit transcriptional machinery to drive expression of BET sensitive genes. Apabetalone inhibits BET bromodomains, causing release from chromatin and downregulation of BET sensitive gene expression. Yellow star size: selectivity of apabetalone for BD2 Acknowledgment: Contributions to this figure by Dr. Eric Campeau, Dr. Olesya Kharenko & Dr. Sylwia Wasiak
Apabetalone ’s Novel & Unique Mechanism CRISPR: genome editing The mechanism is based on cutting and pasting undesired/desired sequences into or out of the DNA, thereby altering the gene sequence and then re-introducing the modified DNA into the body Apabetalone Mechanism is based on changing the levels of disease causing proteins by regulating their expression at the gene level Traditional drug therapies Focus on modifying the activity of one disease protein by using an inhibitor or antibody 8
Inhibition of BET Proteins with Apabetalone Reduces Mediators of Vascular Calcification In Vitro and in CKD Patients • In clinical trials, apabetalone mediated reduction of factors & pathways associated with vascular calcification (VC). • Apabetalone reduced expression of markers of transdifferentiation & genes that promote calcification of CAVSMCs. • Apabetalone reduced the number and size of BRD4-rich enhancers, consistent with displacement of BRD4 from chromatin. • BRD4 ChIP-seq identified 38 unique genes associated with CAVSMC transdifferentiation and calcification. • Involvement of BRD4 in CAVSMC transdifferentiation & calcification is a novel discovery. • The impact of apabetalone on biomarkers, renal function, and CVD outcomes in patients with impaired kidney function is being evaluated in the phase 3 BETonMACE trial. Gilham et al, ERA/EDTA 2018
BET inhibition via apabetalone counters extracellular calcium deposition in human CAVSMCs Dimethyl sulfoxide ( DMSO ) is a water miscible solvent that is used extensively for osteoblastogenic activation to induce tissue calcium deposition. Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018
BET inhibition via apabetalone downregulates expression of genes related to vascular calcification in multiple cell types: ↓↓ expression of Alkaline Phosphatase, Osteopontin, Osteoprotegerin Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018
BET inhibition via apabetalone opposes induction of osteogenic markers in human coronary artery vascular smooth muscle cells Alkaline Phosphatase Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018
Apabetalone Downregulates Alkaline Phosphatase (ALP) Expression in Primary Human Hepatocytes ALPL mRNA Expression ALPL mRNA Expression relative to DMSO same time point relative to DMSO same time point 1,2 1,2 1,0 30uM apabetalone 1,0 Fold Change 0,8 Fold Change 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0,0 DMSO 30uM apabetalone 0,0 0 20 40 60 80 48 hours Treatment Time (hours) ALPL • Alkaline phosphatase expression is downregulated by apabetalone in PHH • Downregulation is consistent with reduced levels in patients receiving apabetalone • The mechanism of ALP release into circulation remains unclear Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 13 Nicholls et al Am J Cardiovasc Drugs 2018
Alkaline Phosphatase (ALP, AlkPhos) MW 150 kDa, serum: 20-120 IU/L • A hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. ( dephosphorylation ). • ALP is most effective in an alkaline environment. • ALP is present in all tissues , particularly concentrated in liver, bone, intestinal mucosa and placenta → isozymes: – bone-specific – liver – tissue-nonspecific – placental Haarhaus M, Brandenburg V, Kalantar-Zadeh K, Stenvinkel P and Magnusson P . Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol. 2017 ;13(7):429-442. doi: 10.1038/nrneph.2017.60. PMID: 28502983. URL: https://www.ncbi.nlm.nih.gov/pubmed/28502983 .
Role of Alkaline Phosphatase (ALP) in Tissue & Vascular Mineralization Haarhaus M, Brandenburg V, Kalantar-Zadeh K, Stenvinkel P and Magnusson P . Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol. 2017 ;13(7):429-442. doi: 10.1038/nrneph.2017.60. PMID: 28502983.
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