HDAC Inhibition for Prevention of Fibrosis Following Sepsisinduced AKI John A. Kellum, MD, MCCM Professor of Critical Care Medicine, Medicine, Bioengineering and Clinical & Translational Science Vice Chair for Research Director, Center for Critical Care Nephrology University of Pittsburgh
Consulting: Adrenomed AM Pharma Astellas Astute Medical Atox Bio Baxter Bioporto Cheetah Medical Cytosorbents Davita Eliaz Pharma Elsevier Grifols Hepa Wash Disclosures Mallinckrodt Medibeacon MedScape Mitobridge Novartis NxStage Oncogna PhotoPhage Potrero Singulex Sphingotech Spectral Diagnostics Sulfateq TES Pharma Grant support: Astellas Astute Medical Atox Bio Baxter Bioporto RenalSense TES Pharma Intellectual Property: Astute Medical Cytosorbents PhotoPhage Updated Jan 2019
What is Acute Kidney Injury Affects about 4 million people in the US each year 10% mortality (25% in ICU) Doubles hospital costs: ~45 billion USD annually. AKI is an abrupt (< 7 days) loss of kidney function due to multiple causes: sepsis, drugs, major surgery Currently defined by changes in serum creatinine and/or urine output
Addressable Market Causes of AKI Medication Sepsis Cardiac Surgery Acute Decompensated Heart Failure Non-cardiac surgery Trauma/burns Oncologic disease Hepatorenal syndrome Environmental toxins, plants, insects, animals
Kellum JA et al. Nat Rev Neph 2018
AKI severity determines outcome Patients that recover do rather well Patients that don t recover do poorly Kellum et al. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7.
Kellum JA et al. Nat Rev Neph 2018
Normal Epithelium Cell death Ischemia/ reperfusion Toxins Necrosis Apoptosis Proliferation Fibrosis Epithelial Cell Cycle G2/M Arrest JNK c-jun AP-1 TGF- 1, CTGF secretion TGFB1, CTGF gene transcription Myofibroblast Proliferation Collagen production Bonventre 2011
Requirements for effective AKI Therapeutics Enhance proliferation AND/OR Prevent maladaptive repair Effective post-injury
From Drug Discovery to Renal Repair Zebrafish AKI Mouse AKI Isolation of chemical compounds that influence the embryonic renal progenitor cell field Compounds that ameliorate Acute Kidney injury Hukriede N. et al
Regeneration Recapitulates Development
Identification of a Novel Class of Histone Deacetylase Inhibitors - PTBA PTBA HDAC inhibitor (Class I) Efficient expansion when renal progenitor cells are present Proliferation based expansion Other HDAC inhibitors also expand the renal field de Groh et al., JASN 2010.
% Survival % Survival % Survival % Survival % Survival % Survival Quantitation of PTBA class analogs by zebrafish AKI survival studies POST-Injury Treatment 100 100 100 80 60 *** 80 60 80 60 ** 40 20 V PTBA 0 0 1 2 3 4 5 6 7 Days after gentamicin injection 40 20 V 29 0 0 1 2 3 4 5 6 7 Days after gentamicin injection n.s. 40 20 V 186 0 0 1 2 3 4 5 6 7 Days after gentamicin injection 100 100 100 80 60 # 80 60 * 80 60 40 20 V 25 0 0 1 2 3 4 5 6 7 Days after gentamicin injection 40 20 V 36 0 0 1 2 3 4 5 6 7 Days after gentamicin injection 40 20 V 263 0 0 1 2 3 4 5 6 7 Days after gentamicin injection n.s.
Col1/Gapdh mrna α-sma/gapdh mrna Loxl1/Gapdh mrna Creatinine, mg/dl Percent fibrosis (SR staining) Timing of UPHD186 treatment in severe IR-AKI L-IR 0 #186 50mg/kg #186 50mg/kg R-nephrectomy #186 50mg/kg Creatinine Fibrosis 1 3 7 8 9 28 Days 2.0 1.5 1.0 0.5 * * Vehicle 1-7 3-7 1-3 9 8 7 6 5 4 3 2 * ** 0.0 V 1-7 3-7 1-3 Days of drug treatment 1 0 V 1-7 3-7 1-3 Days of drug treatment 400 350 300 250 200 150 100 50 0 500 450 400 350 * * 300 * 250 * * 200 150 * 100 50 V 1-7 3-7 1-3 0 V 1-7 3-7 1-3 Days of drug treatment Days of drug treatment 35 30 25 20 15 10 5 0 * * * V 1-7 3-7 1-3 Days of drug treatment Skrypnyk, N. I., et al., AJP- Renal 2016
Nephrotoxicity: Aristolochic Acid Chinese Herb (Aristolochia plants) contain a mixture of Aristolochic acids (AA-I>AA-II and AA-IV) Carcinogen (urothelial malignancy; DNA adducts) Chronic tubulointerstitial nephritis Single dose IP AA 5mg/kg in PBS Sirus red staining at 42 days post injection Yang et al. Nature Medicine 2010
Col1/GAPDH mrna SMA alpha/gapdh mrna Lox/GAPDH mrna Kim1/GAPDH mrna Loxl2/GAPDH mrna TGF beta/gapdh mrna Col18/GAPDH mrna Post-injury Treatment ameliorates AKI and reduce fibrosis after AA injury 160" 140" 120" 100" 80" 60" 40" **" *" 60" 50" 40" 30" 20" **" *" 140" 120" 100" 80" 60" 40" **" 20" 10" 20" 0" 0" 0" 1200" 1000" 800" 600" 400" 200" 0" **" *" 1400" 1200" 1000" 800" 600" 400" 200" 0" *" 40" 35" 30" 25" 20" 15" 10" 5" 0" *" Tatiana Novistkya
Delayed Treatment with UPHD186 Sham CLP + UPHD186 Delayed CLP + UPHD186 Early CLP + Vehicle Wen, et al. Submitted
Opposing effects of Early vs. Delayed Treatment with UPHD186 Inflammation Remolding
Opposing effects of Early vs. Delayed Treatment on EMT Markers
Delayed Treatment Reduces Fibrosis Markers Wen, et al. Submitted
UPHD186
Conclusions Sepsis-associated and Surgery-associated AKI represent prime populations for novel therapeutics Nearly a million patients annually in the US alone, more than 20 million worldwide US addressable market of nearly 5 Billion USD (~100 Billion worldwide) Delayed UPHD186 (well after AKI) is effective in promoting recovery and preventing fibrosis Early anti-inflammatory treatment may not be answer.
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