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Homo sapiens

ABSTRACT: Transcriptomic analysis of healthy donor and Sickle Cell Disease (SCD) hematopoietic stem/progenitor cells

PROVIDER: PRJNA399151 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5952240_1.fastq.gz	Fastqsanger.gz
	SRR5952240_2.fastq.gz	Fastqsanger.gz
	SRR5952231_1.fastq.gz	Fastqsanger.gz
	SRR5952231_2.fastq.gz	Fastqsanger.gz
	SRR5952241_1.fastq.gz	Fastqsanger.gz

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bT87Q-globin gene therapy reduces sickle hemoglobin production, allowing for ex vivo anti-sickling activity in human erythroid cells

Project description:We performed RNA-seq analysis on immortalized human erythroid cell line (HUDEP-2), that had been engineered to carry the sickle cell disease (SCD) mutation (sHUDEP-2), and on healthy donor mobilized CD34+ derived cells after transduction with a control GFP lentivirus and lentivirus expressing βT87Q-globin. Our results show activation of inflammation- and proliferation-related programs, suggesting minimal changes of background gene expression except for βT87Q-globin expression and endogenous β/βs-globin suppression.

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Editing the Sickle Cell Disease Mutation in Primary Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates

Project description:Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle Cell Disease (SCD) is an ideal model to investigate the potential use of gene editing to transvert a single point mutation at the β-globin locus (HBB). We compared the activity of ZFNs and CRISPR/Cas9 for editing and homologous donor templates delivered as single-stranded oligodeoxynucleotides (ssODN), adeno-associated virus serotype 6 (AAV6), integrase-deficient lentiviral vectors (IDLV) and adenovirus 5/35 serotype (Ad5/35) to transvert the base-pair responsible for SCD in HBB in primary human CD34+ HSPCs. We found that the ZFNs and Cas9 directed similar frequencies of nuclease activity. In vitro, AAV6 led to the highest frequencies of homology-directed repair (HDR), but levels of base-pair transversions were significantly reduced when analyzing cells in vivo in immune-deficient mouse xenografts, with similar frequencies achieved with either AAV6 or ssODN. AAV6 also caused significant impairment of colony-forming progenitors and human cell engraftment. Gene correction in engrafting hematopoietic stem cells may be limited by the capacity of the cells to mediate HDR, suggesting additional manipulations may be needed for high efficiency gene correction in HSPCs

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Transcriptomic analysis of healthy donor and Sickle Cell Disease (SCD) hematopoietic stem/progenitor cells

Project description:Human hematopoietic stem/progenitor cells (HSPCs) were either collected from bone marrow or mobilized from healthy donors and SCD patients. We performed RNA-seq analysis on RNA extracted from purified CD34+ HSPCs coming from the different sources to compare their gene expression profiles.

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Project description:β-hemoglobinopathies are the most common genetic disorders worldwide. In sickle cell disease (SCD) a single mutation (E6V) in the b-globin (HBB) gene results in dysfunctional hemoglobin protein, while in β-thalassemia, over 300 mutations distributed across the HBB gene are known to reduce the production of β-globin and cause severe anemia. A genetic engineering approach that replaces the whole HBB gene is an ideal strategy to rescue HBB expression for most genotypes but is technically challenging as the insert cannot be homologous to the endogenous gene and codon-optimized, intron-less sequences may not reconstitute adequate HBB levels. Here, we developed a novel approach for a “one-size-fits-all" HBB gene repair strategy using CRISPR-Cas9 which successfully addresses these problems. First, our DNA donor design avoids sequence homology through a diverged HBB coding sequence and second, incorporates heterologous introns from the fetal g-globin gene, further reducing homology to endogenous HBB while mimicking its intron composition. Screening DNA donors with various heterologous globin introns, polyadenylation signals and truncated sequences, identified a heterologous intron DNA donor that highly expresses β-globin and rescued β-globin expression in two in vitro hemoglobinopathy models in hematopoietic stem and progenitor cells (HSPCs). Furthermore, healthy donor HSPCs modified with this HBB gene replacement approach showed successful engraftment in immunodeficient mice at 16 weeks. In summary, we developed a universal HBB gene replacement strategy that results in physiological b-globin production, offering a potential differentiated approach for treating patients with β-thalassemia, SCD or compound heterozygous individuals.

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