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RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

ABSTRACT: RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

PROVIDER: PRJNA883694 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21684802_1.fastq.gz	Fastqsanger.gz
	SRR21684802_2.fastq.gz	Fastqsanger.gz
	SRR21684803_1.fastq.gz	Fastqsanger.gz
	SRR21684803_2.fastq.gz	Fastqsanger.gz
	SRR21684804_1.fastq.gz	Fastqsanger.gz

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RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

Project description:Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein AAV transgene expression is silenced using the clinically validated modality of chemically modified short interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies.

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RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes.

Project description:Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein hepatocyte-directed AAV transgene expression is silenced using the clinically validated modality of chemically modified small interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies.

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Project description:RNA interference (RNAi)-based gene therapy is a promising strategy for dominant neuropathological conditions. Adeno-associated virus (AAV) vectors are used to deliver RNAi triggers into the central nervous system. The safety of the AAV-RNAi drugs should be closely addressed due to unintended effects on the transcriptome and associated toxicity. In this study, we developed a mutation-specific gene therapy candidate called AAV-sh1500 for the neurodevelopmental disorder caused by the GNAO1 c.607G>A (p.G203R) variant. We assessed the non-intended changes in gene expression induced by AAV infection, activation of RNAi machinery, and sh1500 off-target effects in patient-specific GABAergic neurons in vitro. RNAseq analysis identified 19 downregulated and 59 upregulated genes in neurons treated with AAV-sh1500 compared to non-infected cells. AAV transduction and RNAi activation were found to be the main contributors to the differentially expressed genes. Furthergene ontology analysis showed that AAV transduction downregulates genes related to neuronal differentiation pathways, while RNAi affects genes associated with the apoptotic and protein phosphorylation pathways. The sh1500 sequence-dependent effects were limited to 8 genes. Among these genes, upregulation of SERPINE1, FIP1L1-PDGFRA, PALM2-AKAP2, and COL1A1 has been previously observed in a variety of tumors except the central nervous system. Dysregulation of other off-targets has not been described in pathological processes.

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