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HBB Gene Presentation
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HBB Gene, Beta-Globin Protein, & Sickle Cell Anemia
Grace Bourassa, Kyra Defosses, Saayeh Zarei
HBB gene
Chromosome 11
"Instructions" for creation of Beta-Globin (MedlinePlus)
Protein: Beta-Globin (Hemoglobin subunit)
HBB Gene and its Mutations: Beta-Globin, the spread of oxygen, Sickle Cell Disease, B-Thal, CRISPR
In red blood cells -->
oxygen molecules -->
spreads oxygen
Crucial for health of our entire body
Basis for how we function as a whole
Mutations
Mutations
Sickle
Cell Disease
- Often, Beta-globin superseded by hemoglobin S
- Causes disarray with certain amino acids --> valine instead of glutamic
acid
- Hemoglobin S and C can also replace the original subunits --> another form of SCD
- Sickled cells have shorter lifespan --> anemia
- Painful
- Cells characterized as "rigid" (MedlinePlus)
Beta-Thalassemia
- Negatively impacts core of beta-globin
- Scarcity upon scarcity
- Alteration (point mutation) or deletion of a nucleotide
- B+ = Less beta-globin
- B0 = No beta-globin
What can these diseases lead to?
- Death, anemia, skeletal abnormalities, vaso-occlusive episodes, harm to organs
Potential Remedies
Options:
CRISPR?
Homology-Directed Repair (HDR)
Supports homology-directed repair -->
can make more accurate changes to the mutated gene
- Specifically the mutation of exon 1 and intron 2 and the deletion on exon 2
Bone Marrow Transplantation
Red Blood Cell Transfusion
"Genome inserting-lentiviral vectors"
(Liuhong C, et al)
“Donor DNA template specific for each type HBB mutation [must be] provided” (Liuhong C, et al)
Current Research
Actively looking for new solutions to sickle cell anemia
Current Applications:
CRISPR Cas-9 system in direct and indirect treatments of sickle cell anemia
CRISPR and the Cas-9 gene are essential in current clinical trials
Being used in studies to increase treatments with in vitro options
Fetal Hemoglobin Therapy
Fetal Hemoglobin Function
Fetal Hemoglobin(Hbf) is the main oxygen carrier protein in fetus
1
Developmentally silenced in adults
2
Fetal Hemoglobin inhibits sickle cell hemoglobin from forming blockage chains
3
Currently looking at deactivating the inhibitors of the gene that encodes for Hbf
4
Subjects in clinical trials had good short term reactions and elevated Hbf expression
5
Need more long term data and further research
Red Blood Cell CRISPR Editing
CRISPR Cas-9 Editing in vitro for Red Blood Cells
4
Using CRISPR to edit immature blood cells called erythroblasts
1
Current patients with sickle cell anemia need frequent blood transfusions
5
2
Edited blood cells to remove many of the antigens that cause alloimmunization
Need consistent transfusions of a compatible blood type with major and minor blood groups
6
3
Past experiments have promising results with in vitro developments
Alloimmunization occurs in 2-5% of the general population
Occurs in around 30% of sickle cell transfusions
Implications
Economic considerations
--> Cost of treatment
--> Who is covered?
--> How will others pay?
Ethical and Economic Considerations:
Affordability, treatment side effects
Ethical considerations
--> Treatment risks
--> Patient suffering
Ethics
Ethical Considerations
--> Trial: SCD + b. Thalassemia patients treated with CRISPR to target BCL11A
--> Results: repressed adult hemoglobin and made more fetal hemoglobin
--> After 15 months: 80% allele editing, over 20% decrease in sickled
hemoglobin, no vaso-occlusive episodes, and no need for blood transfusions
--> Serious side effects: pneumonia, liver disease, and sepsis
--> Over 100 total documented side effects
Questions to ask from this trial:
--> Is progression of the science worth 100 complications?
--> Is it worth trading one condition for
another that must be
treated immediately?
--> What complications could occur after one year for patients?
Affordability
People in USA with SCD: 100,000
Annual cost of SCD: $42,200/person
Affordability
People with SCD on Medicaid: 55,000
CRISPR/gene therapy: $1.85 million/person
Proposed Medicaid members eligible for treatment: <5,500
Now is the time!
Questions?
Citations
DeMartino P, Haag M B, Hersh A R, Caughey A B, and Roth J A. 2021. A Budget Impact
Analysis of Gene Therapy for Sickle Cell Disease. JAMA Pediatr. 617-623.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985816/
Demirci S, Leonard A, Essawi K, Tisdale JF. 2021. CRISPR-Cas 9 to induce fetal hemoglobin for the treatment of sickle cell disease. Mol Ther Methods Clin Dev. 23(1):276-285
Frangoul H, Altshuler D, Cappellini M D, Chen Y, Domm J, Eustace B K, Foell J, de la Fuente
J, Grupp S, Handgretinger R, et al. 2021. CRISPR-Cas9 Gene Editing for Sickle Cell Disease
and b-Thalassemia. NE J Med. 252-260. https://www.nejm.org/doi/full/10.1056/NEJMoa2031054
Gene Therapy of Beta-Thalassemia and Sickle Cell Disease. SCT Med. 7(1): 87-97 .https://doi.org/10.1002/sctm.17-0066
Hawksworth J, Satchwell TJ, Meinders M, Daniels DE, Regan F, Thornton NM, Wilson MC, Dobbe JGG, Streekstra GJ, Tarkarnsangak K, Heesom KJ, Anstee DJ, Frayne J, Tonye AM. 2018. Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing. EMBO Mol Med. 10(6):e8454
Liuhong C, Hao B Vasiliki M, Yongxing G, Chaoxia H, Yanfei W, You-Chuan J, You W, Armaan Q, et al. A Universal
Approach to Correct Various HBB Hene Mutations in Human Stem Cells for
Dec. 2, 2022. MedlinePlus, National Library of Medicine (NIH). Bethesda, MD: National Library of Medicine; [2022 Dec 2; accessed
2023 Feb 19]. https://medlineplus.gov/genetics/gene/hbb/
2020 July 1. MedlinePlus, National Library of Medicine (NIH). Bethesda, MD: National Library of Medicine; [2020 July 1; accessed
2023 Feb 19]. https://medlineplus.gov/genetics/condition/sickle-cell-disease/
2022 Dec 2. MedlinePlus, National Library of Medicine (NIH). Bethesda, MD: National Library of Medicine; [2020 July 1; accessed
2023 Feb 19]. https://medlineplus.gov/genetics/condition/beta-thalassemia/
Stuart O, Daniel B. 2019. Emerging Genetic Therapy for Sickle Cell Disease. Annu. Rev. Med. 70:257-71.
https://www.annualreviews.org/doi/pdf/10.1146/annurev-med-041817-125507
Images:
2023. Molecular Devices. San Jose, CA: Molecular Devices; [accessed 2023 Feb 19].
https://www.moleculardevices.com/applications/gene-editing-with-crispr-engineering
Health Services, Alberta. “Sickle Cell Disease.” MyHealth.Alberta.ca Government of Alberta Personal Health Portal,
myhealth.alberta.ca/Health/Pages/conditions.aspx?hwid=hw254173.
Zahir A, Ashwag S, Khalid S, Radwa K, Abdulrahman A, Muhammad T, Norhan H, Haroon B, Ahad K, Sami H, et al. 2020. Fusion of
the Cas9 endonuclease and the VirD2 relaxase facilitates homology-directed repair for precise genome engineering in rice.
Comm. Bio. 3(44).
https://www.nature.com/articles/s42003-020-0768-9#Sec9
Frangoul H, Altshuler D, Cappellini M D, Chen Y, Domm J, Eustace B K, Foell J, de la Fuente
J, Grupp S, Handgretinger R, et al. 2021. CRISPR-Cas9 Gene Editing for Sickle Cell Disease
and b-Thalassemia. NE J Med. 252-260. https://www.nejm.org/doi/full/10.1056/NEJMoa2031054
Froedtert & the Medical College of Wisconsin. Sickle Cell Disease Symptoms. accessed 2021 Feb 21.
https://www.froedtert.com/sickle-cell-disease/symptoms