Genetically Modified Autologous Induced Pluripotent Stem Cell for

Hematology Disorders Treatment: Current and Future Challenges

Makhyan Jibril Al-Farabi1, Rofida Lathifah2
1

Graduate School, Master of Biomedicine, Faculty of Medicine, Brawijaya University, Malang, Indonesia
2

Faculty of Medicine, Airlangga University, Surabaya

ABSTRACT

Introduction
Gene therapy has been applied in a variety of experimental models of genetic disorder
especially hematology disorder with high prevalence such as sickle cell disease, thalassemia and
hemophilia. Sickle cell and thalassemia has been treated with bone marrow transplant, HSC
(hematopoietic stem cell) transplant or -globin genes correction, while hemophilia use FVIII or
FIX gene correction. Nevertheless, these approach facing many challenges such as difficulty to
obtain donor for transplant, difficulties of manipulating HSC ex vivo, and low -globin
correction from direct gene therapy. Therefore, a novel approach that can solve these problem
should be developed.
Objectives
To summarize progress of blood disorder gene therapy with emphasis on iPSCs (Induced
Pluripotent Stem Cells) potency and highlighting the future challenges.
Method
We are conducting reviews from multiple journal related with hematology disorder, gene
therapy and iPSCs. Selected studies will be subjected to a more refined quality assessment by
use of general critical appraisal guides and design-based quality checklists. These detailed
quality assessments will be used for exploring heterogeneity and informing decisions regarding
suitability of review article.
Result

The groundbreaking invention of induced pluripotent stem cells (iPSCs) has provide
researchers a unique tool to develop novel method for gene therapy with autologous cells.
Autologous somatic cells from can be modified by transcription factors of Oct4, Sox2, Klf4, and
c-myc to be a pluripotent state, Gene repair of -globin, FVIII or FIX can be done far easier in
autologous iPSCs. Moreover, it has been proven that gene correction procedures did not impair
the full pluripotentiality of iPSCs. Therefore, its possible to transfect autologus iPSCs to repair
its gene abnormalities then culture it into bioreactor to mass produce the cell. iPSCs then
stimulated with HoxB4 protein to convert it into autologous-repaired HSC that can be
transplanted to the patient. Recent clinical reports support the great promise of this kind of
approach but also highlight the limitations of the technologies used to date. Including inability
to accurately measure genotoxicity from the gene therapy, immune activation against the viral
vector or the gene-engineered cells and risk of tumorigenesis caused by undifferentiated
ESCs/iPSCs.
Conclusion
Autologous iPSCs can be repaired for its genetic disorder, multiplied into bioreactor, then
convert it into transplantable HSC to treat hematologic disorder. Limitation should be well
researched in the future to prevent further side effect especially genotoxicity and tumorigenesis
potency.
Keyword: Autologous gene therapy, Hemophilia, iPSCs, SCD, Thalassemia