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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

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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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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

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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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