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

Autor: Gupta P; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Goswami SG; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Kumari G; Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India., Saravanakumar V; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India., Bhargava N; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India., Rai AB; Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India., Singh P; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Bhoyar RC; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India., Arvinden VR; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Gunda P; Thalassemia and Sickle Cell Society- Kamala Hospital and Research Centre, Shivarampally, Hyderabad, India., Jain S; Thalassemia and Sickle Cell Society- Kamala Hospital and Research Centre, Shivarampally, Hyderabad, India., Narayana VK; Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India., Deolankar SC; Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India., Prasad TSK; Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India., Natarajan VT; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Scaria V; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Singh S; Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India. shailjasingh@mail.jnu.ac.in., Ramalingam S; CSIR- Institute for Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, India. sivaramalingam@igib.res.in.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. sivaramalingam@igib.res.in.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 27; Vol. 15 (1), pp. 1794. Date of Electronic Publication: 2024 Feb 27.
DOI: 10.1038/s41467-024-46036-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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