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MRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

ABSTRACT: mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

PROVIDER: PRJNA817206 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18344902_1.fastq.gz	Fastqsanger.gz
	SRR18344902_2.fastq.gz	Fastqsanger.gz
	SRR18344903_1.fastq.gz	Fastqsanger.gz
	SRR18344903_2.fastq.gz	Fastqsanger.gz
	SRR18344904_1.fastq.gz	Fastqsanger.gz

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mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

Project description:Large genes including several CRISPR-Cas modules, such as gene activators (CRISPRa), require dual adeno-associated viral (AAV) vectors for efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids and in vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, supplementation of ABCA4 (6.8 kb) via REVeRT improves retinal degeneration and function in a mouse model of inherited blindness. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications.

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mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy.

Project description:Large genes including several CRISPR-Cas modules like gene activators (CRISPRa) require dual adeno-associated viral (AAV) vectors for an efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids, and in vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, REVeRT enabled the reconstitution of full-length ABCA4 after intravitreal injection in a mouse model of Stargardt disease. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications.

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Project description:Maddalena et al. showed that the limited DNA transfer capacity (~4.7kb) of adeno associated viral (AAV) vectors can be expanded up to 14kb with triple AAV vectors for the efficient expression of the therapeutic CDH23 (10.1kb) and ALMS1 (12.5kb) genes.

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Project description:Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an HDR template. We also examine the utility of Nme2Cas9 target sites in the vector for self-inactivation. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice. These results will enable single-vector AAVs to achieve diverse therapeutic genome editing outcomes.

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Project description:A truncated reverse transcriptase enhances prime editing by split AAV vectors

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AAV-mediated genome editing is influenced by the formation of R-loops.

Project description:Recombinant adeno-associated viral vectors (rAAV) hold a natural ability to stimulate homologous recombination (AAV-HR). Moreover, they are also reported to randomly integrate into numerous locations throughout the genome. Here, we describe DNA/RNA immune precipitation sequencing (DRIP-seq) studies in HEPA1-6 cells and whole murine liver to detect genomic r-loops. Through genetic and pharmacological manipulation of r-loops formation, we showed a significant enhancement of AAV-HR. Notably, we were able to detect different levels of r-loops along the Albumin locus. Both in vitro and in vivo experiments showed that the 3’ end of Albumin (high r-loops) is efficiently edited by AAV-HR, whereas the upstream region (low r-loops) did not result in any detectable vector integration. In addition, we were also able to find an interesting correlation between previously reported off-target rAAV integration and r-loop enriched genomic regions. Thus, we conclude that highly transcribed genes accumulate high levels of r-loops, and this could lead to rAAV vector genome integration. These findings may shed light on mechanisms for improving the safety and efficacy of genome editing and may enhance our ability to predict regions most susceptible to insertional mutagenesis with canonical rAAV vectors.

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