Leveraging Multi-Omics Approaches and Advanced Technologies to Unravel the Molecular Complexities, Modifiers, and Precision Medicine Strategies for Hemoglobin H Disease.

Publisher: Blackwell Country of Publication: England NLM ID: 8703985 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0609 (Electronic) Linking ISSN: 09024441 NLM ISO Abbreviation: Eur J Haematol Subsets: MEDLINE

Publication: <2005->: Oxford : Blackwell
Original Publication: Copenhagen : Munksgaard, c1987-

Precision Medicine*/methods ; Genomics*/methods ; alpha-Thalassemia*/genetics ; alpha-Thalassemia*/therapy ; alpha-Thalassemia*/diagnosis ; Proteomics*/methods ; Metabolomics*/methods; Humans ; Computational Biology/methods ; Disease Management ; Gene Editing ; Biomarkers ; Genetic Predisposition to Disease ; Multiomics

Hemoglobin H (HbH) disease, a form of alpha-thalassemia, poses significant clinical challenges due to its complex molecular underpinnings. It is characterized by reduced synthesis of the alpha-globin chain. The integration of multi-omics and precision medicine holds immense potential to comprehensively understand and capture interactions at the molecular and genetic levels. This review integrates current multi-omics approaches and advanced technologies in HbH research. Furthermore, it delves into detailed pathophysiology and possible therapeutics in the upcoming future. We explore the role of genomics, transcriptomics, proteomics, and metabolomics studies, alongside bioinformatics tools and gene-editing technologies like CRISPR/Cas9, to identify genetic modifiers, decipher molecular pathways, and discover therapeutic targets. Recent advancements are unveiling novel genetic and epigenetic modifiers impacting HbH disease severity, paving the way for personalized precision medicine interventions. The significance of multi-omics research in unraveling the complexities of rare diseases like HbH is underscored, highlighting its potential to revolutionize clinical practice through precision medicine approaches. This paradigm shift can pave the way for a deeper understanding of HbH complexities and improved disease management.
(© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

K. M. Musallam , S. Rivella , E. Vichinsky , and E. A. Rachmilewitz , “Non‐Transfusion‐Dependent Thalassemias,” Haematologica 98, no. 6 (2013): 833–844.
D. J. Weatherall , “The Inherited Diseases of Hemoglobin Are an Emerging Global Health Burden,” Blood 115, no. 22 (2010): 4331–4336.
V. Kaleva , K. Petrova , and M. Dimova , “Non‐Transfusion‐Dependent Thalassaemia,” Pediatriya 57, no. 1 (2017): 17–22.
Y. C. Lee , C. T. Yen , Y. L. Lee , and R. J. Chen , “Thalassemia Intermedia: Chelator or Not?,” International Journal of Molecular Sciences 23, no. 17 (2022): 9928.
R. Galanello and A. Cao , “Gene Test Review. Alpha‐Thalassemia,” Genetics in Medicine 13, no. 2 (2011): 83–88.
E. P. Vichinsky , “Clinical Manifestations of α‐Thalassemia,” Cold Spring Harbor Perspectives in Medicine 3, no. 5 (2013): a011742.
S. Kong , R. Li , Y. Tian , et al., “Single‐Cell Omics: A New Direction for Functional Genetic Research in Human Diseases and Animal Models,” Frontiers in Genetics 13 (2023): 1006084.
A. T. Taher , D. J. Weatherall , and M. D. Cappellini , “Thalassaemia,” Lancet 391, no. 10116 (2018): 155–167.
D. Songdej and S. Fucharoen , “Alpha‐Thalassemia: Diversity of Clinical Phenotypes and Update on the Treatment,” Thalassemia Reports 12, no. 4 (2022): 203–217.
C. L. Harteveld and D. R. Higgs , “α‐Thalassaemia,” Orphanet Journal of Rare Diseases 5 (2010): 13.
V. Viprakasit , S. Ekwattanakit , S. Riolueang , et al., “Mutations in Kruppel‐Like Factor 1 Cause Transfusion‐Dependent Hemolytic Anemia and Persistence of Embryonic Globin Gene Expression,” Blood 123, no. 10 (2014): 1586–1595.
V. G. Sankaran and M. J. Weiss , “Anemia: Progress in Molecular Mechanisms and Therapies,” Nature Medicine 21, no. 3 (2015): 221–230.
E. Lionetti , R. Bonfanti , G. Forni , et al., “Molecular Basis and Genotype‐Phenotype Correlation of Beta‐Thalassemia in the Italian Population,” Genes (Basel) 8, no. 11 (2017): 326.
D. E. Bauer , S. C. Kamran , and S. H. Orkin , “Reawakening Fetal Hemoglobin: Prospects for New Therapies for the β‐Globin Disorders,” Blood 120, no. 15 (2012): 2945–2953.
D. R. Higgs , J. D. Engel , and G. Stamatoyannopoulos , “Thalassaemia,” Lancet 379, no. 9813 (2012): 373–383.
S. L. Thein , “Molecular Basis of β Thalassemia and Potential Therapeutic Targets,” Blood Cells, Molecules & Diseases 70 (2018): 54–65.
E. A. Traxler , Y. Yao , Y. D. Wang , et al., “A Genome‐Editing Strategy to Treat β‐Hemoglobinopathies That Recapitulates a Mutation Associated With a Benign Genetic Condition,” Nature Medicine 22, no. 9 (2016): 987–990.
Ö. Aldemir , “The Genetic Aspect of Thalassemia: From Diagnosis to Treatment,” in Thalassemia and Other Hemolytic Anemias (London: IntechOpen, 2018).
D. H. K. Chui , S. Fucharoen , and V. Chan , “Hemoglobin H Disease: Not Necessarily a Benign Disorder,” Blood 101, no. 3 (2003): 791–800.
S. Farashi and C. L. Harteveld , “Molecular Basis of α‐Thalassemia,” Blood Cells, Molecules & Diseases 70 (2018): 43–53.
P. Patsali , P. Papasavva , C. Stephanou , et al., “Short‐Hairpin RNA Against α‐Globin (HbA‐sh3) for the Treatment of β‐Thalassemia: In Vitro and In Vivo Validation Studies,” Haematologica 103, no. 9 (2018): e403–e407.
M. H. Steinberg , D. H. Chui , G. J. Dover , P. Sebastiani , and A. Alsultan , “Fetal Hemoglobin in Sickle Cell Anemia: A Glass Half Full?,” Blood 123, no. 4 (2014): 481–485.
M. D. Cappellini , A. Cohen , J. Porter , A. Taher , and V. Viprakasit , eds., Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT), 3rd ed. (Nicosia, Cyprus: Thalassaemia International Federation, 2014).
C. Jin , B. Lee , L. Shen , and Q. Long , “Integrating Multi‐Omics Summary Data Using a Mendelian Randomization Framework,” Briefings in Bioinformatics 23, no. 6 (2022): bbac359.
E. Vichinsky , “Non‐Transfusion‐Dependent Thalassemia and Thalassemia Intermedia: Epidemiology, Complications, and Management,” Current Medical Research and Opinion 32, no. 1 (2016): 191–204.
S. Rivella , “β‐Thalassemias: Paradigmatic Diseases for Scientific Discoveries and Development of Innovative Therapies,” Haematologica 100, no. 4 (2015): 418–430.
R. Galanello and R. Origa , “Beta‐Thalassemia,” Orphanet Journal of Rare Diseases 5 (2010): 11.
E. Khandros and M. J. Weiss , “Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis,” Hematology/Oncology Clinics of North America 24, no. 6 (2010): 1071–1088.
A. T. Taher , K. M. Musallam , and M. D. Cappellini , “β‐Thalassemias,” New England Journal of Medicine 384, no. 8 (2021): 727–743.
D. E. Bauer and S. H. Orkin , “Hemoglobin Switching's Surprise: The Versatile Transcription Factor BCL11A Is a Master Repressor of Fetal Hemoglobin,” Current Opinion in Genetics & Development 33 (2015): 62–70.
A. T. Neff , “Current and Emerging Therapies for the Beta‐Hemoglobinopathies Hematology,” American Society of Hematology. Education Program 2010 (2010): 136–141.
D. Darghouth , B. Koehl , J. F. Heilier , et al., “Metabolomic and Proteomic Profile of Red Blood Cells in Hemoglobin SC Disease,” Blood 117, no. 14 (2011): e57–e67.
S. Fucharoen and V. Viprakasit , “Hb H Disease: Clinical Course and Disease Modifiers,” Hematology 2009, no. 1 (2009): 26–34.
A. J. Kihm , Y. Kong , W. Hong , et al., “An Abundant Erythroid Protein That Stabilizes Free α‐Haemoglobin,” Nature 417, no. 6890 (2002): 758–763.
H. Li and R. Durbin , “Fast and Accurate Short Read Alignment With Burrows‐Wheeler Transform,” Bioinformatics 25, no. 14 (2009): 1754–1760.
V. Lionetti , G. D. Aquaro , S. Simi , et al., “Evaluation of Myocardial Remodeling in Patients With β‐Thalassemia Major by Using Cardiac MR Imaging,” Radiology 285, no. 2 (2017): 469–480.
L. Lisowski , A. P. Dane , K. Chu , et al., “Selection and Evaluation of Clinically Relevant AAV Variants in a Xenograft Liver Model,” Nature 557, no. 7706 (2018): 508–512.
V. G. Sankaran and S. H. Orkin , “The Switch From Fetal to Adult Hemoglobin,” Cold Spring Harbor Perspectives in Medicine 3, no. 1 (2013): a011643.
V. G. Sankaran , J. Xu , T. Ragoczy , et al., “Developmental and Species‐Divergent Globin Switching Are Driven by BCL11A,” Nature 460, no. 7259 (2009): 1093–1097.
K. M. Musallam , A. T. Taher , and E. A. Rachmilewitz , “β‐Thalassemia Intermedia: A Clinical Perspective,” Cold Spring Harbor Perspectives in Medicine 2, no. 7 (2012): a013482.
R. Dickerhoff , “Non‐Transfusion‐Dependent Thalassemia (NTDT)—Therapy,” Oncology Research and Treatment 39, no. Suppl 3 (2016): 41–44.
J. B. Dupont , “Genetic Diseases in the Omics Era,” Molecular Therapy 29, no. 8 (2021): 2577–2578.
R. Njeim , B. Naouss , R. Bou‐Fakhredin , A. Haddad , and A. Taher , “Unmet Needs in β‐Thalassemia and the Evolving Treatment Landscape,” Transfusion Clinique et Biologique 31, no. 1 (2024): 101754.
X. Sun , X. Lv , Y. Yan , et al., “Hypoxia‐Mediated Cancer Stem Cell Resistance and Targeted Therapy,” Biomedicine & Pharmacotherapy 130 (2020): 110623.
B. E. Suwito , A. S. Adji , J. S. Widjaja , et al., “A Review of CRISPR Cas9 for SCA: Treatment Strategies and Could Target β‐Globin Gene and BCL11A Gene Using CRISPR Cas9 Prevent the Patient From Sickle Cell Anemia?,” Open Access Macedonian Journal of Medical Sciences 11, no. 2023 (2023): 1–12.
A. Tantiworawit , S. Dumnil , N. Osataphan , et al., “The Pros and Cons of Splenectomy in Transfusion Dependent Thalassemia Patient,” Blood 132, no. Suppl 1 (2018): 4865.
S. A. Waggoner and S. A. Liebhaber , “Regulation of α‐Globin mRNA Stability,” Experimental Biology and Medicine (Maywood, N.J.) 228, no. 4 (2003): 387–395.
J. Wang , A. Shi , and J. Lyu , “A Comprehensive Atlas of Epigenetic Regulators Reveals Tissue‐Specific Epigenetic Regulation Patterns,” Epigenetics 18, no. 1 (2023): 2159711.
D. J. Weatherall , J. Old , J. Longley , et al., “Acquired Haemoglobin H Disease in Leukaemia: Pathophysiology and Molecular Basis,” British Journal of Haematology 38, no. 3 (1978): 305–322.
L. Zhang , H. Hongping , and W. Qin , “Relationships Between Beta Thalassemia and Polymorphism of BCL11A Gene,” Acta Medica Mediterranea 36, no. 1 (2020): 391–396.
D. E. Bauer , C. Brendel , K. Luk , et al., “Curative Approaches for Sickle Cell Disease and β‐Thalassemia: Challenges and Future Directions,” Blood 139, no. 24 (2022): 3527–3544.
S. Mettananda , R. J. Gibbons , and D. R. Higgs , “α‐Globin as a Molecular Target in the Treatment of β‐Thalassemia,” Blood 125, no. 24 (2015): 3694–3701.
G. J. Kato , F. B. Piel , C. D. Reid , et al., “Sickle Cell Disease,” Nature Reviews Disease Primers 4 (2018): 18010.
F. B. Piel , M. H. Steinberg , and D. C. Rees , “Sickle Cell Disease,” New England Journal of Medicine 376, no. 16 (2017): 1561–1573.
G. Lettre and D. E. Bauer , “Fetal Haemoglobin in Sickle‐Cell Disease: From Genetic Epidemiology to New Therapeutic Strategies,” Lancet 387, no. 10037 (2016): 2554–2564.
S. Lobitz , P. Telfer , E. Cela , et al., “Newborn Screening for Sickle Cell Disease in Europe: Recommendations From a Pan‐European Consensus Conference,” British Journal of Haematology 183, no. 4 (2018): 648–660.
M. J. Telen , “Beyond Hydroxyurea: New and Old Drugs in the Pipeline for Sickle Cell Disease,” Blood 127, no. 7 (2016): 810–819.
M. D. Hoban , S. H. Orkin , and D. E. Bauer , “Genetic Treatment of a Molecular Disorder: Gene Therapy Approaches to Sickle Cell Disease,” Blood 127, no. 7 (2016): 839–848.
S. Kapoor , J. A. Little , and L. H. Pecker , “Advances in the Treatment of Sickle Cell Disease,” Mayo Clinic Proceedings 93, no. 12 (2018): 1810–1824.
Y. Chen , Y. Zhang , Y. Zhang , et al., “Advances in Gene Therapy for β‐Thalassemia,” Blood Reviews 54 (2023): 100895.
J. Kuo , Y. Kuo , C. Chiu , et al., “The Role of Iron Chelation Therapy in Thalassemia: A Review,” Expert Review of Hematology 17, no. 1 (2024): 1–12.

Keywords: gene‐editing; genomics; hemoglobin H disease; molecular modifiers; multi‐omics; precision medicine

0 (Biomarkers)

Date Created: 20241010 Date Completed: 20241105 Latest Revision: 20241105

20250114

10.1111/ejh.14319

39385444