Slide 1: Sickle Cell Disease Education and Therapeutic Management
Sickle Cell Disease Education and Therapeutic Management MIT-ALL-0340/November 2025
Slide 2: Table of Contents
Table of Contents 3 Background & SCD Overview 8 Pathophysiology of SCD 14 Burden of SCD 21 Unmet Needs in SCD and Emerging Treatments 25 Summary SCD, sickle cell disease. 2 MIT-ALL-0340/November 2025
Slide 3: Background & SCD Overview
Background & SCD Overview SCD, sickle cell disease. MIT-ALL-0340/November 2025 3 MIT-ALL-0340/November 2025
Slide 4: In Sickle Cell Disease, Mutations in the β-Globin Gene Lead to HbS Polymerization and Morphological Changes in RBCs
In Sickle Cell Disease, Mutations in the β-Globin Gene Lead to HbS Polymerization and Morphological Changes in RBCs Morphologic changes Sickle cell disease1,2 HbS polymerization1 (e.g., RBC sickling)1,3 Group of inherited disorders ▪ Drives a cascade of pathologic processes ▪ Impair normal biorheolo
Slide 5: SCD Is Among the Most Common Inherited Conditions Globally
SCD Is Among the Most Common Inherited Conditions Globally1 ▪ SCD impacts ~100,000 individuals in the United States and >7,000,000 ▪ SCD incidence shows a wide range4,*: individuals globally1,2 • 0.07 per 1000 in nonendemic areas • It is more common in people descended from regions where malaria is
Slide 6: SCD Is Diagnosed Primarily Using Hb Protein Analysis Methods
SCD Is Diagnosed Primarily Using Hb Protein Analysis Methods1 Protein analysis for Advantages1 Disadvantages1 SCD diagnosis Timing ofTiming of screening screening and diagnosis and diagnosis Electrophoresis Reliable and May be costly and distinguishes most types requires skilled of SCD technicians N
Slide 7: Supplemental and Emerging Methods for SCD Diagnosis
Supplemental and Emerging Methods for SCD Diagnosis Supplemental methods1,2 Newer methods1 ▪ Genetic testing is not routine, but may be used when Hb protein analysis is High-power image processing inconclusive or when unusual variants are detected ▪ Automated, high-power images of RBCs ▪ The followi
Slide 8: Pathophysiology of SCD
Pathophysiology of SCD SCD, sickle cell disease. MIT-ALL-0340/November 2025 8 MIT-ALL-0340/November 2025
Slide 9: Key Pathophysiological Processes in SCD
Key Pathophysiological Processes in SCD ▪ HbS mutation in β-globin chains results in multiple synergistic HbS polymerization1,3,4 Hemolysis Sickling pathological processes1,2: HbS ⇀ ↽ ⇀ ↽ Hb polymer bundles a. HbS polymerization β6 triplet codon GAG ⟶ GTG HbS polymers are rigid and distort RBCs, cau
Slide 10: Polymerization of Deoxygenated HbS Tetramers Leads to RBC Sickling
Polymerization of Deoxygenated HbS Tetramers Leads to RBC Sickling1,2 ▪ The substitution of glutamic acid with valine at the 6th position of the β-globulin polypeptide chain (dbSNP identifier Rs334) drives Hb polymerization in SCD2,3 GAG is replaced GTG hydrophilic Glu by hydrophobic Val G G AC T C
Slide 11: Intravascular Hemolysis Contributes to Vasculopathy, Endothelial Dysfunction, and Vaso-Occlusion in SCD
Intravascular Hemolysis Contributes to Vasculopathy, Endothelial Dysfunction, and Vaso-Occlusion in SCD Intravascular hemolysis: Contributes to Vaso-occlusion: Adhesion proteins on chronic vasculopathy, platelet activation, and the activated endothelium interact with Intravascular hemolysis1,2 pulmo
Slide 12: Hemolysis Also Activates Danger-Associated Molecular Pattern Signaling and Sterile Inflammation
Hemolysis Also Activates Danger-Associated Molecular Pattern Signaling and Sterile Inflammation Sterile inflammation: Pathogen-free inflammation mediated by free heme and DAMPs2,4 ▪ Heme activates TLR4 on endothelial cells and DAMPs (heme, ATP, HMGB1)2,5,6 monocyte/ macrophages1 • Extracellular ATP
Slide 13: Anemia in SCD Can Damage Organs and Impair General Health
Anemia in SCD Can Damage Organs and Impair General Health Cardiovascular ▪ Several factors contribute to anemia in dysfunction SCD, including extravascular and intravascular hemolysis, reduced erythropoiesis due to decreased EPO ↓Hb Low Hb levels Pulmonary production, and bone or bone marrow hyperte
Slide 14: Burden of SCD
Burden of SCD SCD, sickle cell disease. 14 MIT-ALL-0340/November 2025 MIT-ALL-0340/November 2025
Slide 15: SCD Is Associated With Increased Mortality
SCD Is Associated With Increased Mortality SCD has an annual global mortality burden of 376,000 individuals All-age total sickle disease mortality rate, males and females, 20211 In the United States, SCD continues to be a source of early mortality among African Americans2 75 40 Reduced overall life
Slide 16: Various Factors Underlie the Phenotypic Features of SCD
Various Factors Underlie the Phenotypic Features of SCD Acute pain Acute chest syndrome Vaso- Hyposplenism Sickling occlusion Osteonecrosis Nephropathy Vaso-occlusion Inflammation Increased VCAM-1 Hypercoagulability and adhesion molecule expression Pulmonary hypertension Hemolysis Priapism Decreased
Slide 17: SCD Causes Painful Episodes And Fatigue
SCD Causes Painful Episodes And Fatigue Vaso-occlusive Acute pain is the Pain management Patients report pain commonly most common is complex and fatigue as a main occurs in the back reason for challenging in factor negatively and extremities, but hospitalization patients with SCD3 impacting their c
Slide 18: Low Hb Impacts Clinical Outcomes and QOL
Low Hb Impacts Clinical Outcomes and QOL Negative overall clinical outcomes ▪ Low Hb levels are associated with higher incidence of negative clinical outcomes including stroke, silent cerebral infarct, and mortality1 ▪ Anemia can lead to frailty, decreased mobility, and increased risk of hospitaliza
Slide 19: SCD Has a Significant Impact on Patient QOL
SCD Has a Significant Impact on Patient QOL ▪ SWAY is a multicountry, cross-sectional survey assessing the impact of SCD on the daily lives of 2145 patients between April and October 20191 • Patients with SCD reported disruptions in both Emotional and Overall Function domains SCD patients reporting
Slide 20: Economic Burden in SCD Goes Beyond Patient OOP Costs
Economic Burden in SCD Goes Beyond Patient OOP Costs A retrospective observational study of EHR claims from 2005 through 2015 estimated the annual incremental economic burden of SCD at1,*: $10,079 per patient: A meta-analysis and systemic Outpatient costs accounted for 38% literature search of publi
Slide 21: Unmet Needs in SCD and Emerging Treatments
Unmet Needs in SCD and Emerging Treatments SCD, sickle cell disease. MIT-ALL-0340/November 2025 21 MIT-ALL-0340/November 2025
Slide 22: SCD Diagnosis May Be Missed in Individuals Not Evaluated by Newborn Screening
SCD Diagnosis May Be Missed in Individuals Not Evaluated by Newborn Screening Insights and considerations on patterns of SCD diagnosis Widespread adoption of newborn screening in the United States and most of Europe allows for the early detection of SCD1-3 Globally, lack of universal newborn screeni
Slide 23: Available SCD Treatments Offer Clinical Benefits, But Various Factors May Limit Implementation
Available SCD Treatments Offer Clinical Benefits, But Various Factors May Limit Implementation1 Hydroxyurea2-4 L-glutamine6 Crizanlizumab7 Exagamglogene autotemcel8 Lovotibeglogene autotemcel9 Mechanism of Blocks interactions between Induction of HbF Reduction in RBC oxidative stress CRISPR/Cas9 gen
Slide 24: Emerging SCD Treatments Target Various Signaling Pathways
Emerging SCD Treatments Target Various Signaling Pathways Therapeutic strategy: Therapeutic strategy: Therapeutic strategy: Inhibition of HbS Target downstream PK activation1 polymerization2-5 pathways1,6,7 ▪ ATP increase improves RBC health and survival ▪ Gene modification to reverse the effects of
Slide 25: Summary
Summary MIT-ALL-0340/November 2025 25 MIT-ALL-0340/November 2025
Slide 26: Summary
Summary SCD is a group of inherited disorders SCD diagnoses are primarily made using In SCD, HbS polymerization drives a characterized by mutations in the protein analysis methods, including cascade of pathologic processes β-globin gene; SCD impacts ~100,000 electrophoresis, isoelectric focusing, an