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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)
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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
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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
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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
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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
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CRISPR restoration of fetal hemoglobin
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https://seekingalpha.com/article/4131294-cutting-edge-gene-therapies-beta-thalassemia-breakthroughs
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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!!
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Gene therapy Drugs (e.g. iron chelators)
Are there new treatments on the horizon?
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YES!!
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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