Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

Park, Chul‐Yong; Kim, Duk Hyoung; Son, Jeong Sang; Sung, Jin Jea; Lee, Jaehun; Bae, Sangsu; Kim, Jong Hoon; Kim, Dong Wook; Kim, Jin-Soo

doi:10.1016/j.stem.2015.07.001

Cited by 268 publications

(201 citation statements)

References 34 publications

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“…47,48,58 Introduction of 2 engineered nucleases can result in targeted deletion or inversion, duplication, local indels at nuclease cleavage sites, or translocations/ chromosomal rearrangements. [60][61][62][63][64][65][66][67][68][69][70][71][72][73] Here, we review genome-editing approaches for genetic correction and disruption strategies for the b-hemoglobinopathies as summarized in Figure 1 and Table 1.…”

Section: Introductionmentioning

confidence: 99%

Customizing the genome as therapy for the β-hemoglobinopathies

Canver

Orkin

2016

Blood

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Despite nearly complete understanding of the genetics of the β-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats–based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34+ hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the β-globin disorders.

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Section: Introductionmentioning

confidence: 99%

Customizing the genome as therapy for the β-hemoglobinopathies

Canver

Orkin

2016

Blood

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“…23 There is considerable enthusiasm in the molecular biology community concerning the utility of this technology, and the momentum of CRISPRCas9 advances has been dramatic. 24 However, despite the fact that mutant coagulation gene editing has already been reported in vitro, 25 several critical limitations to this technology remain. The achievable efficiency of mutation correction is still low, and perhaps more problematic is the potential for damaging off-target editing events elsewhere in the genome.…”

Section: Gene Therapy Strategies For Coagulation Disordersmentioning

confidence: 99%

Gene Therapy for Coagulation Disorders

Swystun

Lillicrap

2016

Circulation Research

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Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright. (Circ Res.

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“…However, the challenge is to invert a much larger region that is eight times more prevalent than aforementioned 140-kbp inversion. Park et al successfully used the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system to correct these regions in patient-specific iPSCs (82). Combining these gene editing tools with iPSC technology would provide a source of endothelial progenitor cells for transplantation therapies.…”

Section: Cell Therapymentioning

confidence: 99%