Human AlphoidtetO Artificial Chromosome as a Gene Therapy Vector for the Developing Hemophilia A Model in Mice

Ponomartsev, Sergey V.; Sinenko, Sergey; Skvortsova, Elena V.; Liskovykh, Mikhail; Voropaev, Ivan N; Savina, Maria M; Kuzmin, Andrey A.; Kuzmina, Elena Yu; Kondrashkina, Alexandra M; Larionov, Vladimir; Kouprina, Natalay; Tomilin, Alexey

doi:10.3390/cells9040879

Cited by 16 publications

(22 citation statements)

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“…The iPSC cells showed stable expression of the F8 gene and the vector remained independent. However, the production process is still very complicated, the induced HAC loses its integrity in the following generations of cells, and the FVIII still has a low level of production (168).…”

Section: Gene Therapiesmentioning

confidence: 99%

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

et al. 2021

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Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short halflife, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

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Section: Gene Therapiesmentioning

confidence: 99%

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

et al. 2021

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“…They used HAC/iPSC-based strategies for the treatment of hemophilia A monogenic disease. This study is the first step towards treatment development for hemophilia A monogenic disease with the use of a new generation of the synthetic chromosome vector—the alphoid tetO -HAC [ 28 ].…”

Section: Stem Cell-based Therapymentioning

confidence: 99%

“…This Special Issue includes both research [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and reviews articles [ 10 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] which cover wide ranges of stem cell research: adult stem cells, cancer stem cells, pluripotent stem cells, and complex 3D organoid/cell aggregate models [ 26 , 27 , 33 ], with the focuses on stem cell biology/technology [ 10 , 23 , 24 , 25 , 26 , 31 , 32 , 34 ], and stem cell-based disease modeling [ 10 , 27 , 29 , 31 , 33 , 38 , 43 ] and cell therapy [ 24 , 28 , 30 , 32 , 35 , 36 , 37 , 39 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Stem Cell-Based Disease Modeling and Cell Therapy

Bai

2020

Cells

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Stem cell science is among the fastest moving fields in biology, with many highly promising directions for translatability. To centralize and contextualize some of the latest developments, this Special Issue presents state-of-the-art research of adult stem cells, induced pluripotent stem cells (iPSCs), and embryonic stem cells as well as cancer stem cells. The studies we include describe efficient differentiation protocols of generation of chondrocytes, adipocytes, and neurons, maturation of iPSC-derived cardiomyocytes and neurons, dynamic characterization of iPSC-derived 3D cerebral organoids, CRISPR/Cas9 genome editing, and non-viral minicircle vector-based gene modification of stem cells. Different applications of stem cells in disease modeling are described as well. This volume also highlights the most recent developments and applications of stem cells in basic science research and disease treatments.

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“…HACs made using synthetic centromeric DNA have been extensively characterized and improved over the last decade [2][3][4][5] . They now represent an important tool to study epigenetic regulation of centromere structure and function 2,[6][7][8][9][10] , to study full-length gene functions in mutant animal or human cells 5,[11][12][13][14][15][16] , to measure chromosome instability (CIN) and identify new targets for cancer therapy [17][18][19] . Also, synthetic HACs do not interfere with embryogenesis in mouse, making them a promising tool for future gene therapeutic studies 15 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of Complex DNA Rearrangements During Early Stages of HAC Formation

Pesenti

Liskovykh

Okazaki

et al. 2020

Preprint

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AbstractHuman Artificial Chromosomes (HACs) are important tools for epigenetic engineering, for measuring chromosome instability (CIN) and possible gene therapy. However, their use in the latter is potentially limited because the input HAC-seeding DNA can undergo an unpredictable series of rearrangements during HAC formation. As a result, after transfection and HAC formation, each cell clone contains a HAC with a unique structure that cannot be precisely predicted from the structure of the HAC-seeding DNA. Although it has been reported that these rearrangements can happen, the timing and mechanism of their formation has yet to be described. Here we synthesized a HAC-seeding DNA with two distinct structural domains and introduced it into HT1080 cells. We characterized a number of HAC-containing clones and subclones to track DNA rearrangements during HAC establishment. We demonstrated that rearrangements can occur early during HAC formation. Subsequently, the established HAC genomic organization is stably maintained across many cell generations. Thus, early stages in HAC formation appear to at least occasionally involve a process of DNA shredding and shuffling that resembles chromothripsis, an important hallmark of many cancer types. Understanding these events during HAC formation has critical implications for future efforts aimed at synthesizing and exploiting synthetic human chromosomes.

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Human AlphoidtetO Artificial Chromosome as a Gene Therapy Vector for the Developing Hemophilia A Model in Mice

Cited by 16 publications

References 56 publications

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

Stem Cell-Based Disease Modeling and Cell Therapy

Analysis of Complex DNA Rearrangements During Early Stages of HAC Formation

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