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Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

ABSTRACT: Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

PROVIDER: PRJNA976238 | ENA |

REPOSITORIES: ENA

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Efficient targeted integration in proliferating patient hepatocytes for inherited liver diseases

Project description:Hepatocyte transplantation has shown great potential for treating inherited liver diseases. However, its prolonged clinical therapeutic efficacy is still hindered by serious immune rejection from the host immunological responses to the allogeneic hepatocytes and there is still no an effective approach to generate clinically available autologous hepatocytes for transplantation therapy. Here, we report advanced medium conditions that allow 10,000-fold expansion of primary human hepatocytes from patients suffering inherited liver diseases, providing a new autologous hepatocytes source to this problem. Moreover, we developed a CRISPR–Cas9 genome-targeting system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homology-independent large donor (greater than three kilobase) to achieve efficient targeted integration at the AAVS1 safe harbor locus in patient-derived proliferating human hepatocytes (ProliHHs). We further applied this strategy to correct a pathogenic OTC and FAH mutation in ProliHHs and demonstrated improved gene expression, while preserving cell viability for the expansion and purification of edited ProliHHs. Importantly, these edited ProliHHs repopulate into injured mouse liver at a level near to primary human hepatocytes, and they undergo maturation to successfully treat the tyrosinemia mouse model following transplantation in vivo. Thus, this study provides a new autologous hepatocyte therapy techniques that enable large-scale expansion and ex vivo gene correction in patient-derived transplantable ProliHHs, which holds the potential for modeling and treating human liver disease.

2023-09-12 | GSE233425 | GEO

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Inherited diseases in cattle

Project description:Inherited disease mutations in cattle

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Changes in the level of expression of genes involved in the pathogenic mechanisms in rare, inherited metabolic diseases.

Project description:Inherited metabolic diseases belong to the group of rare diseases (so called ‘orphan diseases’) whose incidence is less than 1: 5 000 live births. Among these diseases the lysosomal storage diseases (LSD) are also distinguished, which are caused by disorders in the lysosomal system resulting from the mutations in the genes coding for lysosomal hydrolases, cofactors, enzymes involved in the posttranslational processing, and proteins present in the lysosomal membrane. Although about 70 LSD are recognized so far, their pathomechanism is almost unknown. Hitherto existing results of scientific investigations indicate that different cellular pathways and events are involved in the pathogenic processes: autophagy, apoptosis, toxic action of lyso- derivatives of lipid compounds, disordered Ca2+ ions intracellular homeostasis, secondary storage of macromolecular compounds, signal transduction, inflammatory processes, deficient by-products and many more. We are especially interested in the explanation of pathomechanisms of Gaucher disease and Niemann-Pick type C disease (for the latter disease there is no therapy officially accepted). In this project we aim to experimentally explain: - which cellular pathways and mechanisms are activated and inactivated in cells originating from patients with different LSD and healthy individuals - are there differences in genes expression in different diseases - are gene expression changes related to known and observed biochemical and clinical changes.

2019-04-23 | GSE124283 | GEO

2-Guanidino-quinazoline promotes efficient translational suppression of nonsense mutations responsible of Human genetic diseases

Project description:2-Guanidino-quinazoline promotes efficient translational suppression of nonsense mutations responsible of Human genetic diseases

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Changes in the level of expression of genes involved in the pathogenic mechanisms in rare, inherited metabolic diseases.

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RNA-seq transcriptional profiling in primary human hepatocytes, short- and long-term cultured Proliferating human hepatocytes (in vitro/in vivo)

Project description:One of the major challenges of cell therapy is manufacturing of the effective seed cells, which inevitably requires the expansion of cells in vitro. Although considerable progresses have been achieved in expansion of primary human hepatocytes (PHH) in vitro, the transplantation efficiency of proliferating human hepatocytes was decreased with the extended culture. The mechanism of declined transplantation is not clear.Here, we found that long-term cultured proliferating human hepatocytes (lc-ProliHH) significantly upregulated chemokines and proinflammatory cytokines associated with innate immune response. Moreover, lc-ProliHH elicited robust recruitment of macrophages and neutrophils at early stage of transplantation, and being cleared by macrophages caused the engraftment efficiency reduction.Based on these findings, we designed to treat recipient with Dexamethasone (Dex), which decreased the response of innate immune cells and significantly increased the transplantation efficiency to a level approximate to PHH in the liver-injured mice. Furthermore, ProliHH organoid reduced the expression of cytokine genes and behaved close to mature hepatocyte, and as a result, ameliorated their transplantation efficiency as well.

2024-01-25 | GSE184448 | GEO

Project description:Inherited diseases in cattle

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