Ερυθροποιητικοί Tροποποιητές μετά την Ερυθροποιητίνη Γ. Βασιλόπουλος MD hd Καθηγητής Παθολογίας- Αιματολογίας Ιατρική Σχολή, Πανεπιστήμιο Θεσσαλίας & Υπεύθυνος Ερευνητικής Ομάδας Εργαστήριο Γενετικής και Γονιδιακής Θεραπείας Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Erythropoiesis Epo dependence?????? TGF- β
What is TGFβ? LTs contain 40-100x TGF- β compared to other Ossues
TGF- β Blood, Vol 88, No 1 (July l), 1996: pp 82-88
CFU GM BFUe Blood, Vol81, No 11 (June 1). 1993: pp 2891-2897
The TGFβ Family 1. TGF- β 2. AcOvins 3. Inhibins 4. Nodal 5. Bone morphogenic proteins (BMs) 6. Growth- and- differenfafon factors (GDFs)
The TGF- β family of receptors (Ser/Thr kinase) Type I n=7 (acfvin receptor- like kinases, ALK1-7) Type II n=5 LIGAND acfvin/nodal TGF- β BM Cell Membr ActR- IIA ActR- IIB ALK4 ALK7 TGF- β- RII ALK1 ALK5 BMR- II ActR- IIA ActR- IIB ALK2 ALK3 ALK6
SMADs are Used for Signal TransducOon acfvin/nodal TGF- β BM Cell Membr Receptor SMAD ActR- IIA ActR- IIB ALK4 ALK7 Smad2 Smad3 TGF- β- RII Smad6 Smad7 ALK1 ALK5 BMR- II ActR- IIA ActR- IIB ALK2 ALK3 ALK6 Smad1 Smad5 Smad8 Receptor SMAD Smad4 R Smad Nucl Membr Target Gene
The SMAD Family Gene Homologs (Cloned as growth mutants - wrong body paeerning) C Elegans small (small size worm) Drosophila mad (mothers against decapentaplegic) Mammals small + mad = SMAD The receptor- regulated Smads R- SMAD 1, 2, 3, 5, 8 The common- mediator Smad co- SMAD 4 The inhibitory Smads I- SMAD 6, 7 TGF- β / AcOvin R- SMAD 2, 3 BM R- SMAD 1, 5, 8
TGF- β Canonical and AlternaOve aths in Erythropoiesis TGF- β Cell Membr TGF- β- RII ALK1 ALK5 Receptor SMAD Smad2 Smad3 Smad4 Smad2/3 TIF 1γ Smad2/3 GROWTH INHIBITION Erythroid DifferenOaOon Nucl Membr Cell 2006, 125;929
TGF- β and HSC Heterogeneity HSC heterogeneity My vs Ly potenfal In older ndividuals Myeloid bias Young vs Old HSC 19% of differenfally expressed genes in TGF- β path Cell Stem Cell. 2010;6(3):265-278.
TGF- β Signalling in Myelofibrosis HSC High TO Blood. 2002;100(10): 3495-3503.
TGF- β signalling in Myelodysplasia Higher TGF- β In MDS OveracFve SMAD2 Reduced SMAD7 High mir21 (SMAD7 target) Blood. 2008;112(8): 3434-3443. J Hematol Oncol. 2013;6:50.
TGF- β signalling in Myelodysplasia: InhibiOon of ALK5 improves MDS colony formaoon TGF- β TGF- β- RII ALK5 SD- 208 SD- 208 100nM SD- 208 200nM BLOOD, 15 OCTOBER 2008 VOLUME 112, NUMBER 8
TGF- β signalling has leiotropic Effects Cell context dependent Shows dosage effects aaern formafon in embryogenesis Tissue homeostasis Cardiovascular diseases ConnecFve Fssue (Marfan) ReproducFve system Cleb palate Tumors (prostate, breast, colon, pancreas) OSTEOOROSIS (high TGF- β)
InhibiOon of ActR- IIA (ACE011): SOmulates New Bone FormaOon. ACE 011 TGF- β BM Cell Membr ActR- IIA ActR- IIB ALK4 ALK7 Smad2 Smad3 TGF- β- RII ALK1 ALK5 BMR- II ActR- IIA ActR- IIB ALK2 ALK3 ALK6 Smad1 Smad5 Smad8 Receptor SMAD Increase in osteoblastogenesis Decrease in osteoclasoc acovity
«ACE- 011 is a novel agent with biological evidence of both an increase in bone formafon and a decrease in bone resorpfon. ACE- 011 may be an effecfve therapy in a variety of diseases involving bone loss.» Max % increase Hgb: 18% from baseline JOURNAL OF BONE AND MINERAL RESEARCH Volume 24, Number 4, 2009
InhibiOon of ActR- IIB (ACE 536): Hgb Effect ACE 536 TGF- β BM Cell Membr ActR- IIA ActR- IIB ALK4 ALK7 TGF- β- RII ALK1 ALK5 BMR- II ActR- IIA ActR- IIB ALK2 ALK3 ALK6 Smad1 Smad2 Smad3 Smad5 Smad8 Receptor SMAD
~ 80% roporoon of normal subjects with >1g/dL increase in Hgb AJH 89(7);p766, 2014
ASH 2016 Abstract 3168 Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in afents with Low- Intermediate Risk MyelodysplasFc Syndromes (MDS): Long- Term Results from hase 2 ACE- MDS Study IWG HI- E (hematol improve Erythroid) 85% LTB pts 79% HTB pts 83% RS+ pts 90% EO < 200 U/L 86% EO 200-500 U/L 50% EO > 500 U/L TRANSFUSION INDEENDENCE 58% EO < 200 U/L 50% EO 200-500 U/L 33% EO > 500 U/L
ASH 2016 Abstract 3168
ASH 2016 Abstract 3168
ASH 2016 Abstract 851 Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with β- Thalassemia Transfusion dependent: 20/24 (83%) 33% decrease in transfusion burden 16/24 (67%) 50% decrease in transfusion burden DuraFon of response ranged from 12 to 48+ weeks. Non- Transfusion dependent: 21/27 (78%) 1.0 g/dl 15/27 (56%) 1.5 g/dl
Luspatercept (ACE- 536): ü Πραγματική ελπίδα στα πολυ- μεταγγιζόμενα LR MDS και β- θαλασσαιμία ü Καλά ανεκτό ü Ευκολία στη χορήγηση (SC q15d) ü Βάθος ανταπόκρισης ü Ενεργό σε τελικά στάδια κυττ. διαφοροποίησης ü Πιθανά προβλ. από τη δραστικότητα του μονοπατιού σε πολλούς ιστούς
Masayo Takahashi (ΜD, Ophthalmo..) RIKEN Center for Developmental Biology (CDB) Kobe, Japan ES- cell- based treatments for refnal diseases Age Related Macular DegeneraOon 2013: sheets of refnal pigment epithelium (RE) cells for a clinical trial 1; went ahead but aber injecfon: MUTATIONS in is 2; HALT No RBC producoon plan LogisOcs problems
Erythromer (EM), a Nanoscale Bio- SyntheOc ArOficial Red Cell: roof of Concept and In Vivo Efficacy Results Hemorrhagic shock Model, During the 1st hour: 1. resolufon of both lacfc acidosis (3.2±1.5 v 8.2±2.1 mm) 2. elevated AV O2 difference (24±11 v 67±23%) 3. improved brain po2 (30.5±1.4 v 17.2±1.3 Torr); ASH 2016: Abstract #1027