Zissis C. Chroneos, Ph.D.Associate Professor of Pediatrics, Microbiology and Immunology

An Endemic Genetic Disease in Mediterranean People

Cooley’s Anemia

Harrisburg Cooley’s Anemia Task Force:Dr. Michael Billys, Ed.D.Dr. Zissis Chroneos, Ph.D.Mr. Christ P. Megoulas, NREMT-PFr. Michael Varvarelis, Cathedral Dean (Holy Trinity, Camp Hill, PA)

AKA: (β) Thalassemia Major

Fatal Genetic Blood Disorder

Has Plagued the Mediterranean People for 2000 Years

What is Cooley’s Anemia?

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Thomas BentonCooley

1921

>2 million people

MediterraneanMiddle Eastern

Asian

Unaware parent

carriers at risk of affecting

children

History of β-Thalassemia

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Cooley’s anemia is only one form of β-Thalassemia that require continued community and public health vigilance

Community education, awareness, and support have worked before to decrease incidence and improve the prognosis of Cooley’s Anemia

Why do we care?

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Screening Test in Greek Americans Sparks AHEPA’s Ride For Life Journey

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“..because of our better treatments and the fact that very few new patients with thalassemia majorare being born in Connecticut– in part, I think, because of our testing and education – our patientswith thalassemia are much older. When I started my Thalassemia Clinic in New Haven in 1968,their average age was 7 years; it’s now more than 35 years ..” Howard Pearson, 2000

Biology of Thalassemia

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Red Blood Cell (RBC)

HemoglobinO2 Carrier Protein

α-Chainβ-Chain

α-Chain β-Chain

Biology of Thalassemia

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Shang and Xu Best Practice & Research Clinical Obstetrics and Gynaecology 39 (2017) 3e15

Point Mutation in α or β gene

Thalassemia

Hemoglobin Changes in Early Development

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Cavazzana et al, Molecular Therapy Vol. 25 No 5 May 2017

Timeline of Hemoglobin Switch

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Onset of

symptoms

Shang and Xu Best Practice & Research Clinical Obstetrics and Gynaecology 39 (2017) 3e15

α -Thalassemia β-Thalassemia

Clinical Classification

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Silent/Minima Mild to no anemiaDiagnosed by DNA testing in familiesGenerally rare, more common in Greece

1.

2.

3.

Minor

Major

Mild anemia“Healthy Carriers” can pass trait on to children

Severe anemic symptoms between 18 mo – 3 yrsPaleness, Insomnia, Appetite Loss, Vomiting Frequent Blood Transfusions

Four Types of β-Thalassemia:

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Mild to moderate anemia, increased risk after infection

Jaundice

Gallstones

Skeletal Changes

Iron Overload

Growth Impairment Hepatosplenomegaly

Metabolic Abnormalities

Pulmonary hypertension

Clots

4. Intermedia (TI)

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Clinical differentiation of Thalassemia Major and Intermedia

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Asadov et al, International Journal of Hematology, 2018

Inheritance of β-Thalassemia

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Shang and Xu Best Practice & Research Clinical Obstetrics and Gynecology 39 (2017) 3e15

Gene Structure of Thalassemias

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https://goo.gl/images/Ntu7nm

Autosomal Recessive Pattern of Inheritance

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Autosomal Recessive Inheritance

Point mutations causeβ-thalassemia

Prenatal Diagnosis is Essential

Summary of Clinical Points

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There is HOPE: Diagnosis & Treatments

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Thein SL, Blood Cells, Molecules and Diseases, 2018

Hemoglobin

Mean Cell Volume

Mean Cell Hb

Mean Corpuscular Hb Concentration

RBC Distribution Width

Cost: $23.87

Diagnostic Method 1: Complete Blood Count

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Differentiates Thalassemia from Iron-Deficiency

Anemia

Cost: $20-50.00

Diagnostic Method 2: Ferritin Test

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https://clinicalgate.com/haematology-and-oncology/

Test Cost: $154.50

Interpretation Cost: $23.40

Total Cost: $177.90

Diagnostic Method 3: Electrophoresis of Hb

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Dreusy et al, Biomedical Journal 39 (2016), 24e38

Current and Future Therapies for β-Thalassemia

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Recent Success in Gene Therapy Treatment

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Emerging Therapies of β-Thalassemia

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Curative treatmentsBluebird Bio: HBG205 Lentiviral transduction gene therapy to produce functional hemoglobin at Clinical stages 2/3 to treat transfusion dependent Thalassemia. Works better for Thalassemia Intermedia. Most promising therapy so far.

Celgene/Acceleron Pharma: Luspatercept promotes red blood cell development in non-transfusion dependent Thalassemia in Phase III Clinical Trial .

Kaidis Pharma: ATIR2102 immunotherapy to alleviate graft versus host disease of allogeneic bone marrow transplant.

Sangamo Therapeutics/CRISPR Therapeutics/ Vertex/Editas Medicine: ST-400/CT001/Cpf1 to repair mutations or replace with fetal hemoglobin by CRISPR editing of patients’ stem cells in early phase with IND approval moved to phase I in Europe.

Non-curative treatmentsLaJolla Pharmaceutical/Protagonist Therapeutics: LJPC-401/PTG-300 synthetichepcidins to alleviate iron overload.

https://seekingalpha.com/article/4131294-cutting-edge-gene-therapies-beta-thalassemia-breakthroughs

CRISPR restoration of fetal hemoglobin

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https://seekingalpha.com/article/4131294-cutting-edge-gene-therapies-beta-thalassemia-breakthroughs

Frequently Asked Questions

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YES!!

Google Images

Am I at risk for carrying the β-Thalassemia trait?

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https://goo.gl/images/3gK0Ad

Genetic Testing

How can I find out if I have the β-Thalassemia trait?

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1 in 4 Children will have β-Thalassemia major

Why should I care if I have the β-Thalassemia trait?

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Prenatal Planning

https://goo.gl/images/rVHXWa

What should I do if I learn I carry the β-Thalassemia trait?

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Mostly Likely Not, Unless β-Thalassemia Intermedia

https://goo.gl/images/DWX7SB

If I carry the β-Thalassemia trait, will it affect my health and activities?

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Potentially:Failure to Thrive

Delayed PubertyAplastic Anemia

Cosmetic ChangesChronic HemolysisHemolytic Anemia

Iron OverloadCardiopulmonary

complicationsβ-Thalassemia Minor

β-Thalassemia Intermedia

https://goo.gl/images/TGXtiQ

Can the Thalassemia minor trait turn into β-Thalassemia major?

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Regular Blood TransfusionsIn some cases: bone marrow transplant, iron chelators

https://goo.gl/images/eXdQkS

Can β-Thalassemia major be treated?

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+ + +Carrier

ScreeningGenetic

CounselingPrenatal

Screening Education

Reduced Incidence:

1:250 1:4000Google Images

Can β-Thalassemia be prevented?

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YES!!

Gene therapy Drugs (e.g. iron chelators)

Are there new treatments on the horizon?

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YES!!

Complex genetic disease with serious complications if left untreated

Family planning, Healthy Pregnancy, Your health and your children’s health matters, Avoid misdiagnosis, Testing is easy.

Education, Awareness, and Support are still needed

Why do we care again?

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1. Survey the community’s interest

2. Organize a community wide campaign

3. Coordinate with Penn State University College of Medicine for the screening

4. Engage with The AHEPA Cooley’s Anemia Foundation and stakeholders

Call to Action for AHEPA Chapter 64

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Thank you!Zissis Chroneos, Ph.D.Associate Professor of Pediatrics