Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells

He, Qiong Qiong; Cheng, Tao; Yuan, Weiping; Ma, Yupo; Jiang, Yongping; Ren, Zhihua

doi:10.24920/j1001-9294.2017.032

Cited by 10 publications

(2 citation statements)

References 39 publications

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“…Use of induced pluripotent stem cells (iPSCs) in this context is also common as they present with similar characteristics to those of embryonic cells but without the bioethical problems associated with them. IPSCs have allowed significant progress in the realm of HA and HB [ 16 , 17 ].…”

Section: Advanced Therapies In Hemophiliamentioning

confidence: 99%

Gene Therapy in Hemophilia: Recent Advances

Rodríguez-Merchán

Pablo-Moreno

Liras

2021

IJMS

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Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

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Section: Advanced Therapies In Hemophiliamentioning

confidence: 99%

Gene Therapy in Hemophilia: Recent Advances

Rodríguez-Merchán

Pablo-Moreno

Liras

2021

IJMS

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“…Other preclinical strategies that are under investigation include insertion of the transgene into the AAVS1 locus 290 , 291 or in the native locus 292 , 293 , 294 , 295 and correction of disease-associated variants 296 , 297 , 298 or large chromosomal rearrangements. 299 , 300 , 301 …”

Section: Main Textmentioning

confidence: 99%

Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease

Ernst

Broeders

Herrero-Hernandez

et al. 2020

Molecular Therapy - Methods & Clinical Development

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We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger nucleases (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, gene editing is applied ex vivo in T cells, transgenic T cell receptor (tTCR)-T cells, or chimeric antigen receptor (CAR)-T cells to improve adoptive cell therapy for multiple cancer types. This involves knockouts of immune checkpoint regulators such as PD-1, components of the endogenous TCR and histocompatibility leukocyte antigen (HLA) complex to generate universal allogeneic CAR-T cells, and CD7 to prevent self-destruction in adoptive cell therapy. In cervix carcinoma caused by human papillomavirus (HPV), E6 and E7 genes are disrupted using topically applied gene editing machinery. In HIV infection, the CCR5 co-receptor is disrupted ex vivo to generate HIV-resistant T cells, CAR-T cells, or hematopoietic stem cells. In β-thalassemia and sickle cell disease, hematopoietic stem cells are engineered ex vivo to induce the production of fetal hemoglobin. AAV-mediated in vivo gene editing is applied to exploit the liver for systemic production of therapeutic proteins in hemophilia and mucopolysaccharidoses, and in the eye to restore splicing of the CEP920 gene in Leber’s congenital amaurosis. Close consideration of safety aspects and education of stakeholders will be essential for a successful implementation of gene editing technology in the clinic.

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In vitro recovery of FIX clotting activity as a marker of highly functional hepatocytes in a hemophilia B iPSC model

et al. 2021

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Background and Aims: Pluripotent stem cell-derived hepatocytes differentiated in monolayer culture are known to have more fetal than adult hepatocyte characteristics. If numerous studies tend to show that this immature phenotype might not necessarily be an obstacle to their use in transplantation, other applications such as drug screening, toxicological studies, or bioartificial livers are reliant on hepatocyte functionality and require full differentiation of hepatocytes. New technologies have been used to improve the differentiation process in recent years, usually evaluated by measuring the albumin production and CYP450 activity. Here we used the complex production and most importantly the activity of the coagulation factor IX (FIX) produced by mature hepatocytes to assess the differentiation of hemophilia B (HB) patient's induced pluripotent stem cells (iPSCs) in both monolayer culture and organoids.Approach and Results: Indeed, HB is an X-linked monogenic disease due to an impaired activity of FIX synthesized by hepatocytes in the liver. We have developed an in vitro model of HB hepatocytes using iPSCs generated from fibroblasts of a severe HB patient. We used CRISPR/Cas9 technology to target the genomic insertion of a coagulation factor 9 minigene bearing the Padua mutation to enhance FIX activity. Noncorrected and corrected iPSCs were differentiated into hepatocytes under both two-dimensional and

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Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells

Cited by 10 publications

References 39 publications

Gene Therapy in Hemophilia: Recent Advances

Gene Therapy in Hemophilia: Recent Advances

Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease

In vitro recovery of FIX clotting activity as a marker of highly functional hepatocytes in a hemophilia B iPSC model

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