Development of pathophysiologically relevant models of sickle cell disease and β-thalassemia for therapeutic studies

Pragya Gupta, Sangam Giri Goswami, Geeta Kumari, Vinodh Saravanakumar, Nupur Bhargava, Akhila Balakrishna Rai, Praveen Singh, Rahul C. Bhoyar, V. R. Arvinden, Padma Gunda, Suman Jain, Vanya Kadla Narayana, Sayali C. Deolankar, T. S. Keshava Prasad, Vivek T. Natarajan, Vinod Scaria, Shailja Singh () and Sivaprakash Ramalingam ()
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Pragya Gupta: CSIR- Institute for Genomics and Integrative Biology
Sangam Giri Goswami: CSIR- Institute for Genomics and Integrative Biology
Geeta Kumari: Jawaharlal Nehru University
Vinodh Saravanakumar: CSIR- Institute for Genomics and Integrative Biology
Nupur Bhargava: CSIR- Institute for Genomics and Integrative Biology
Akhila Balakrishna Rai: Yenepoya (Deemed to Be University)
Praveen Singh: CSIR- Institute for Genomics and Integrative Biology
Rahul C. Bhoyar: CSIR- Institute for Genomics and Integrative Biology
V. R. Arvinden: CSIR- Institute for Genomics and Integrative Biology
Padma Gunda: Thalassemia and Sickle Cell Society- Kamala Hospital and Research Centre, Shivarampally
Suman Jain: Thalassemia and Sickle Cell Society- Kamala Hospital and Research Centre, Shivarampally
Vanya Kadla Narayana: Yenepoya (Deemed to Be University)
Sayali C. Deolankar: Yenepoya (Deemed to Be University)
T. S. Keshava Prasad: Yenepoya (Deemed to Be University)
Vivek T. Natarajan: CSIR- Institute for Genomics and Integrative Biology
Vinod Scaria: CSIR- Institute for Genomics and Integrative Biology
Shailja Singh: Jawaharlal Nehru University
Sivaprakash Ramalingam: CSIR- Institute for Genomics and Integrative Biology

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Ex vivo cellular system that accurately replicates sickle cell disease and β-thalassemia characteristics is a highly sought-after goal in the field of erythroid biology. In this study, we present the generation of erythroid progenitor lines with sickle cell disease and β-thalassemia mutation using CRISPR/Cas9. The disease cellular models exhibit similar differentiation profiles, globin expression and proteome dynamics as patient-derived hematopoietic stem/progenitor cells. Additionally, these cellular models recapitulate pathological conditions associated with both the diseases. Hydroxyurea and pomalidomide treatment enhanced fetal hemoglobin levels. Notably, we introduce a therapeutic strategy for the above diseases by recapitulating the HPFH3 genotype, which reactivates fetal hemoglobin levels and rescues the disease phenotypes, thus making these lines a valuable platform for studying and developing new therapeutic strategies. Altogether, we demonstrate our disease cellular systems are physiologically relevant and could prove to be indispensable tools for disease modeling, drug screenings and cell and gene therapy-based applications.

Date: 2024
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DOI: 10.1038/s41467-024-46036-x

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