03 Aug Patient-Derived Stem Cells May Be Able To Reverse Hemophilia A
Medical Research: What is the background for this study?
Response: Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation.
Medical Research: What are the main findings?
Response: We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia.
Medical Research: What should clinicians and patients take away from your report?
Response: Our results provide a proof of principle for functional correction of large chromosomal inversions in Hemophilia patient-derived induced pluripotent stem cells and suggest potential therapeutic applications in the future.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: We need to prove the safety of patient-derived iPSCs before we move towards clinics.
The safety of iPSCs means to prevent teratoma formation when we do clinical trials.
For that purpose, we need to develop good differentiation protocols into EC cells and to purify the cells as well. In addition, we need much more animal study.
Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9
Cell Stem Cell Available online 23 July 2015
Dong-Wook Kim (2015). Patient-Derived Stem Cells May Be Able To Reverse Hemophilia
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