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Genomic and epigenetics guided identification of tissue-specific genomic safe harbor sites for gene therapy

ABSTRACT: Genomic and epigenetics guided identification of tissue-specific genomic safe harbor sites for gene therapy

PROVIDER: PRJNA762356 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15844822_1.fastq.gz	Fastqsanger.gz
	SRR15844822_2.fastq.gz	Fastqsanger.gz
	SRR15844823_1.fastq.gz	Fastqsanger.gz
	SRR15844823_2.fastq.gz	Fastqsanger.gz
	SRR15844824_1.fastq.gz	Fastqsanger.gz

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Transcriptomes of novel human genomic safe harbor sites for gene and cell therapies

Project description:Bulk RNA-sequencing experiments were performed to analyze the transcriptomic effects of such integrations into two newly established genomic safe harbor sites. Jurkat and HEK293T cells were edited to integrate CMV-mRuby expressing cassette into Rogi2 genomic safe harbor site using Cas9 RNP

2022-02-11 | E-MTAB-11289 | biostudies-arrayexpress

Genomic and epigenetics guided identification of tissue-specific genomic safe harbor sites for gene therapy

Project description:One common strategy in gene and cell therapies requires the integration and stable transcription of transgenes into the host cell genomes. Genomic safe harbors (GSHs) are regions of the genome that can maintain the expression of transgenes without disrupting the transcriptome of host cells. With recent advances in genome editing technology, GSHs play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited candidate GSHs have been identified. In addition, many parameters currently used to identify GSHs are not knowledge based and none of the current available GSHs meet all the ideal safety requirement. In this study, we use the polymorphic mobile element insertions (pMEIs) that naturally occur among healthy human populations to facilitate GSHs searching. By integrating pMEIs with epigenomic signatures and 3D chromatin organization information, we developed a framework to map cell typespecific GSHs. We applied our framework to pMEIs identified in the 1000 Genomes project and GTEX projects and identified novel GSHs Candidates in blood and brain cells. We further validated that a transgene cassette integrated in one novel GSH can be stably transcribed without affecting normal proliferation and differentiation of host cells. We also developed a user-friendly program to search for GSHs in different population and cell types.

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Transcriptomes of novel human genomic safe harbor sites for gene and cell therapies

Project description:Transcriptomes of novel human genomic safe harbor sites for gene and cell therapies

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Genome-wide analysis of gene expression in human iPSCs and NSCs engineered by safe-harbor TALEN-mediated gene targeting

Project description:Human iPSCs and NSCs were engineered by AAVS1 and/or C13 safe-harbor TALENs which mediated targeted integration of various reporter genes at single or dual safe-harbor loci. Multiple clones of targeted human iPSCs were used to compare with parental untargeted NCRM5 iPSCs. Polyclonal targeted human NSCs were used to compare with their parental untargeted NCRM1NSCs or H9NSCs. Total RNA obtained from targeted human iPSCs or NSCs compared to untargeted control iPSCs or NSCs.

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CRISPR-MAD7 Genomic Safe Harbor Sites

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Genomics and epigenetics guided identification of tissue-specific genomic safe harbors.

Project description:BackgroundGenomic safe harbors are regions of the genome that can maintain transgene expression without disrupting the function of host cells. Genomic safe harbors play an increasingly important role in improving the efficiency and safety of genome engineering. However, limited safe harbors have been identified.ResultsHere, we develop a framework to facilitate searches for genomic safe harbors by integrating information from polymorphic mobile element insertions that naturally occur in human populations, epigenomic signatures, and 3D chromatin organization. By applying our framework to polymorphic mobile element insertions identified in the 1000 Genomes project and the Genotype-Tissue Expression (GTEx) project, we identify 19 candidate safe harbors in blood cells and 5 in brain cells. For three candidate sites in blood, we demonstrate the stable expression of transgene without disrupting nearby genes in host erythroid cells. We also develop a computer program, Genomics and Epigenetic Guided Safe Harbor mapper (GEG-SH mapper), for knowledge-based tissue-specific genomic safe harbor selection.ConclusionsOur study provides a new knowledge-based framework to identify tissue-specific genomic safe harbors. In combination with the fast-growing genome engineering technologies, our approach has the potential to improve the overall safety and efficiency of gene and cell-based therapy in the near future.

| S-EPMC9490961 | biostudies-literature

Apoa1, a safe harbor locus for therapeutic genome editing in the liver

Project description:Apoa1, a safe harbor locus for therapeutic genome editing in the liver

| PRJNA641134 | ENA

Therapeutic globin expression in thalassemia patient induced pluripotent stem cells from genomic safe harbors

Project description:The advent of human induced pluripotent stem (iPS) cells enables for the first time the derivation of unlimited numbers of patient-specific stem cells and holds great promise for regenerative medicine. However, realizing the full potential of iPS cells requires robust, precise and safe strategies for their genetic modification. Safe human iPS cell engineering is especially needed for therapeutic applications, as stem cell-based therapies that rely on randomly integrated transgenes pose oncogenic risks. Here we describe a strategy to genetically modify iPS cells from patients with beta-thalassemia in a potentially clinically relevant manner. Our approach is based on the identification and selection of “safe harbor” sites for transgene expression in the human genome. We show that thalassemia patient iPS cell clones harboring a transgene can be isolated and screened according to chromosomal position. We next demonstrate that iPS cell clones that meet our “safe harbor” criteria resist silencing and allow for therapeutic levels of beta-globin expression upon erythroid differentiation without perturbation of neighboring gene expression. Combined bioinformatics and functional analyses thus provide a robust and dependable approach for achieving desirable levels of transgene expression from selected chromosomal loci. This approach may be broadly applicable to introducing therapeutic or suicide genes into patient specific iPS cells for use in cell therapy.

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Apoa1, a safe harbor locus for therapeutic genome editing in the liver

Project description:Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent, broadly applicable, while minimizing risks of off-target integration. In the liver, the Albumin locus is currently the only well characterized site for promoterless transgene insertion. Using an unbiased ChIP-seq approach, we here identify Apolipoprotein a1 (Apoa1) as one of the most highly expressed and accessible loci in mouse and human liver. We target the Apoa1 locus with Adeno-Associated Viral (AAV) delivery of CRISPR/Cas9, and achieve rates of 6 to 16% with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic proteins such as factor IX (FIX) or apolipoprotein E (APOE). Finally, we demonstrate that Apoa1-targeted fumarylacetoacetate hydrolase (FAH) can correct and rescue the severe metabolic liver disease hereditary tyrosinemia type I. In summary, we identify and validate Apoa1 as novel safe harbor site for genome editing therapeutics.

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