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Children’s Cancer and Blood Foundation Laboratories Division of Hematology-Oncology Department of Pediatrics Weill Medical College of Cornell University New York. New approaches to modulate abnormal erythropoiesis and improve the transfusion regimen in ß-thalassemia and sickle cell disease .

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Presentation Transcript
slide1

Children’s Cancer and Blood Foundation Laboratories

Division of Hematology-Oncology

Department of Pediatrics

Weill Medical College of Cornell University

New York

New approaches to modulate abnormal erythropoiesis and improve the transfusion regimen in ß-thalassemia and sickle cell disease

slide2

Heme

Heme

ß-Thalassemia

Adult Hemoglobin

Alpha/Heme Aggregates

Mutations in the beta-globin gene

Consequences of Reduced ß-Globin Chain Production

Anemia

Ineffective

Erythropoiesis

Iron Overload

Erythroid Marrow

Expansion-Splenomegaly

Thrombosis

slide3

Normal vs. stress erythropoiesis

Proliferation

Proliferation

Proliferation

Differentiation

Differentiation

Differentiation

Stress erythropoiesis

Normal

Lenox et al, Blood 2005.

Menon et al. JCI 2006.

Marinkovic et al. JCI 2007.

Harandi et al. JCI 2010.

Ulyanova et al. Blood 2011.

slide4

Stress vs. ineffective erythropoiesis

:

Chronic Stress Erythropoiesis

Stress erythropoiesis

Ineffective

erythropoiesis

Normal

slide5

Ineffective erythropoiesis

Cell death

Anemia

Chronic stress erythropoiesis:

Increased cell proliferation

Reduced cell differentiation

slide6

Epo

EpoR

Jak2

Jak2

Stat5

pJak2

pJak2

Protection from apoptosis

Cell Replication

pStat5

Erythropoiesis: a brief summary

slide7

Jak2: a gene that controls red cell production

Normal Erythropoiesis

Progenitor erythroid cells

Red cell

: pJak2

Cooley’s Anemia

Apoptosis

Libani I. & al, Blood 2008

slide8

Cooley’s Anemia

Ineffective Erythropoiesis

Jak2 Inhibitor

Red cell

Potential effect of Jak2 inhibitors on ineffective erythropoiesis

: pJak2

Libani I. & al, Blood 2008

hypothesis
Hypothesis
  • Can we modulate Jak2 activity to prevent or revert splenomegaly and EMH?
  • Can we use Jak2 inhibitors to ameliorate the transfusion regimen?
  • Can we use Jak2 inhibitors for other transfusion dependent-related disorders, such as sickle cell anemia?
slide10

Administration of a pJak2 inhibitor on mice affected bythalassemia intermedia

Experimentaldesign

TG101209 (TG: 100 or 150 mg/kg/day)or Placebo for10 days

pJak2 inhibitor/ TG101209

Day 11

Day0

Analysis

Luca Melchiorri, Carla Casu& Pedro Ramos

Tg101209(Tg) or Placebo

Daily oral gavage (100 or 150 mg/kg/day) for 10 days

Tg101209(Tg) or Placebo

Daily oral gavage (100 or 150 mg/kg/day) for 10 days

Tg101209(Tg) or Placebo

Daily oral gavage (100 or 150 mg/kg/day) for 10 days

th3/+

th3/+

th3/+

th3/th3

th3/th3

th3/th3

Day -7

Day 0

Day -7

Day 0

Day -7

Day 0

+/- Transfusion (TX)

+/- Transfusion (TX)

+/- Transfusion (TX)

slide11

Reduction of splenomegaly and amelioration ofextramedullaryhematopoiesis without major impact on anemia in animals affected by ß-thalassemiaintermedia

Spleen size (%placebo ctl)

**

***

WT

*

*

*

*

**

Placebo

TG 100

TG 150

Luca Melchiorri, Carla Casu& Pedro Ramos

Placebo

Placebo

Placebo

Placebo

***

***

***

Tg (100)

Tg (100)

Tg (100)

Tg (100)

wt

wt

wt

Tg (150)

Tg (150)

wt

Tg (150)

Tg (150)

Erythroid apoptosis

slide12

Administration of a pJak2 inhibitor to mice affected by ß-thalassemiaintermedia and major in presence of blood transfusion

slide13

Administration of a pJak2 inhibitor in mice affected byß-Thalassemia

TG101209 (TG: 150 mg/kg/day) or Placebofor10 days

Hb

Day

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Blood Transfusion

Analysis

Luca Melchiori, CralaCasu& Pedro Ramos

slide14

Hematological parameters in mice affected by ß-thalassemiaintermediaafter transfusion and TG101209 treatment

CTRL no-TXF

*

*

**

**

*

WT

Carla Casu& Pedro Ramos

slide15

Jak2 inhibitor increases efficacy of transfusion in transfusion dependent mice affected by ß-thalassemia major

*

**

**

**

**

th3/th3

**

Jak2 inhib./TG101209

+ TX

***

***

Placebo + TX

WT

Luca Melchiorri, Carla Casu& Pedro Ramos

slide16

Could we use a similar approach to ameliorate the transfusion regimen in sickle cell anemia?

slide17

Combination of TG101209 with transfusion reduces the number of sickle RBC cells in SickleCell mice

WT

*

Placebo +TX Tg (100) +TX

*

**

Pedro Ramos & Carla Casu

jak2 inhibitors potential applications
Jak2 Inhibitors: Potential Applications

Erythroid progenitors

Circulating thalassemic RBCs

Donor RBCs

ß-Thalassemia Major

Transfusion alone

Transfusion alone

Jak2 inhib. + Transfusion

ß-ThalassemiaIntermedia

Sickle Cell Anemia

Jak2 inhib. + Transfusion

acknowledgments
Acknowledgments

The Edith Wolfson Medical Center, Holon,

Israel

Eliezer A. Rachmilewitz

Chaim Sheba Medical Center,Tel-Aviv University, Israel

Ninette Amariglio

Gideon Rechavi

David Geffen School of Medicine,UCLA, USA

Elizabeta Nemeth

Duke University School of Medicine, Durham, USA

Nancy C Andrews

Johns Hopkins University, Baltimore, USA

Cindy N Roy

New York Blood Center, USA

Yelena Ginzburg

Xiu Li An

Narla Mohandas

Department of Pediatrics - WCMC, New York, USA

Sara Gardenghi

Pedro Ramos

M.Franca Marongiu

Luca Melchiori

Ella Guy

Lori Bystrom

Laura Breda

Carla Casu

Niva Rao

Tom Renaud

Robert W. Grady

Patricia J. Giardina

Sponsors

NIH-The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Cooley’s Anemia Foundation (CAF)

Roche Foundation for Anemia Research (RoFar)

slide21

Conclusions

  • Jak2 plays a major role in controlling IE, splenomegaly and EMH in ß-thalassemia.
  • Using Jak2 inhibitors might be possible to prevent or revert splenomegaly and EMH.
  • Use of Jak2 inhibitors might ameliorate the transfusion regimen in conditions associated with profound ineffective erythropoiesis (i.e. ß-thalassemia major).
  • Use of a tailored dose of Jak2 inhibitors might also be beneficial in transfusionalsickle cell anemia...to be continued
slide22

Ineffective erythropoiesis:

New therapies?

Ineffective erythropoiesis:

excessive cell proliferation coupled with hemichrome formation

Might Jak2 inhibitors be even more effective in combination with therapies that modulate iron metabolism?

slide24

Iron overload and anemia worsen over time in thalassemic mice

Iron overload increases with time in th3/+ mice

Hamp1 is expressed at relatively low levels in iron overloaded th3/+ mice

P < 0.05

2.0

Organ total iron content (ug)

Spleen

1.5

P < 0.01

P < 0.001

P < 0.05

Liver

Liver Hamp1 mRNA level

1.0

P <0.001

0.5

Anemia worsens with time in th3/+ mice

+/+

15.0

0

13.0

+/+

2M

5M

12M

+/+

+/+

+/+

th3/+

th3/+

th3/+

Hemoglobin (g/dL)

11.0

th3/+

9.0

th3/+

12M

5M

2M

7.0

Gardenghi et al. Blood 2007, 109: 5027-35.

2.0

Months

12.0

Sara Gardenghi

slide25

Increased Hepcidin expression leads to extended RBCs lifespan and improved morphology

th3/+

th3/+ control

Florid erythropoiesis & apoptosis

Splenomegaly

Iron overload

Tg-Hamp1/th3

Decreased erythroid iron intake and reduced hemichrome formations

Less apoptosis, extended RBCs lifespan and improved morphology

Amelioration of erythropoiesis and splenomegaly

TgHamp/th3

Sara Gardenghi& Pedro Ramos

slide26

Hemoglobin Levels in Post Splenectomized and Untransfused

ß-Thalassemia Intermedia Patients

12

N = 11

10

8

Hemoglobin (g/dl)

6

4

2

0

0

1

2

4

6

3

5

Time (years post splenectomy)

Splenectomy and Anemia in ß-Thalassemic Patients

Sergios Zacharoulis and Patricia J. Giardina ASH, 2004

slide27

Normal

Patient

Ki67

Ki67+

Glycophorin-A

& spectrin

Increased erythroid cell proliferation in human ß-thalassemic erythroid cells

Amy Chadburn, YiFang-Liu and Patricia J. Giardina