Page 135 - CSIR-IGIB Annual Report 2020-21
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Induced pluripotent stem cell-based disease potential for development of autologous cell
modelling for rare genetic disorders replacement therapy for the above diseases.
A rare disease is a life threatening or chronically
incapacitating disease that affects five people or Therapeutic fetal hemoglobin induction
fewer in 10000 and requires special, combined for the treatment of beta-
efforts to enable patients to be treated effectively. hemoglobinopathies
All rare disease taken together account for about The beta-hemoglobinopathies such as beta-
6-8% of the world population. About 50 % of the thalassemia (BT) and sickle cell anemia (SCA)
rare diseases affect children causing significant are the most common group of monogenic
social and economic burden, while the other half disorders in India. Sickle cell anemia is caused
manifests in adulthood. The total number of rare by a single nucleotide change in β-globin gene
diseases is steadily increasing partly owing to (HBB) but β-thalassemia is caused by more
genetic research to explain disease patterns that
we did not understand before. than 200 different mutations present in the
same gene. Currently, there is no permanent
Whether a disease can be treated or not often cure available for these disorders, except for
depends on scientists’ ability to have a clear bone marrow transplantation. The lack of
understanding of the pathobiology of the disease. available immunologically matched donors
Disease-specific human induced pluripotent stem and toxic side effects from allogenic bone
cells (hiPSCs) can be generated directly from marrow transplantation (BMT), however,
patient cells with the known disease means that allogenic BMT has only been used
characteristics or created using genome-editing to treat a tiny fraction of the patients who
approach to introduce disease causing genetic could benefit. It is well established that fetal
mutations to study the biological response of hemoglobin (HbF) is able to replace adult
those mutations. We have established multiple
induced pluripotent stem cell (iPSC) lines from a hemoglobin (HbA) and alleviate the symptoms
thalassemia major and Gaucher’s disease patients of β-hemoglobin disorders. We have
carrying different genetic mutations. Functional demonstrated a proof-of-concept on
characterization of iPSC demonstrated that these reactivation of fetal hemoglobin using site-
pluripotent stem cells are free of exogenous specific genome engineering in different
reprogramming genes and expressed pluripotent preclinical cellular models. Major advantage
stem cell markers, exhibited a normal karyotype of our approach over gene correction is that it
and held potential for three germ layer involves only non-homologous end joining
differentiation. Currently, we are editing the (NHEJ), which is more efficient and active
disease-causing mutations and creating isogenic throughout cell cycle and high capability than
iPSC lines. The generated iPSC line will be used as homology directed gene repair. Moreover,
a control line, and the disease corrected isogenic
iPSC lines will be valuable for disease modelling. there is no requisite for exogenous HDR
Moreover, gene-corrected iPSC-derived template for this study, which makes
hematopoietic stem progenitor cells also hold substantial difference in terms of genome
engineering or editing efficiency.
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