Long-term transcriptome-wide therapeutic effects of AAV-hpCas13d
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PROVIDER: PRJNA1132169 | ENA |
REPOSITORIES: ENA
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Project description:To fully understand the enduring therapeutic effects of hpCas13d and its potential for clinical translation, comprehensive investigation is needed. In this study, we employed RNA-sequencing to analyze transcriptome alterations in Myh6RH/+ hearts, Myh6RH/RQ hearts, and hpCas13d[RQ]-treated Myh6RH/RQ hearts, aiming to elucidate the molecular mechanisms underlying the regression of cardiac hypertrophy induced by hpCas13d[RQ] treatment.
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Project description:Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration by decreasing the expression of IFNα. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed fifteen days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.
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Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).
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Project description:Adeno-associated viral vectors (AAV) are a leading delivery system for gene therapy in animal models and humans. With several FDA-approved AAV gene therapies on the market, issues related to vector manufacturing have become increasingly important. In this study, we focused on potentially toxic DNA contaminants that can arise from AAV proviral plasmids, the raw materials required for manufacturing recombinant AAV in eukaryotic cells. Typical AAV proviral plasmids are circular DNAs containing a therapeutic gene cassette flanked by natural AAV inverted terminal repeat (ITR) sequences, and a plasmid backbone carrying prokaryotic sequences required for plasmid replication and selection in bacteria. While the majority of AAV particles package the intended therapeutic payload, some capsids instead package the bacterial sequences located on the proviral plasmid backbone. Since ITR sequences also have promoter activity, potentially toxic bacterial open reading frames can be produced in vivo, thereby representing a safety risk. In this study, we describe a new AAV proviral plasmid for vector manufacturing that (1) significantly decreases cross-packaged bacterial sequences; (2) increases correctly packaged AAV payloads; and (3) blunts ITR-driven transcription of cross-packaged material to avoid expressing potentially toxic bacterial sequences. This system may help improve the safety of AAV vector products.
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Project description:BACKGROUND & AIMS: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes that can only be cured with liver transplantation. However, no mechanism-based strategies exist to enhance biliary development in ALGS or other diseases associated with bile duct paucity. We aimed to identify a therapeutic target to address this unmet clinical need. METHODS: Preclinical mouse models of ALGS lacking one copy of Jag1 in germline with or without conditional deletion of one or both copies of Sox9 with Albumin-Cre were used. Sox4 levels were reduced in these models genetically or by using adeno-associated virus serotype 8 (AAV8) vectors driving a Sox4-silencing sequence. Liver histology, biliary tree ink injection, serum chemistry, RNAscope, and single-cell RNA-sequencing (scRNA-Seq) were performed for phenotypic characterization and gene expression analysis. RESULTS: Conditional removal of one copy of Sox4 in the liver significantly improved the liver phenotypes in ALGS mouse models in a Sox9-dependent manner. RNAscope experiments showed an increase in Sox4 expression level and relative abundance of Sox4-Sox9 double-positive cells in early postnatal livers of Jag1-heterozygous mice. scRNA-Seq revealed the appearance of an intermediate hepatobiliary cluster co-expressing Sox4 and Sox9 in Jag1-heterozygous livers. AAV8-mediated Sox4 knockdown, ubiquitously or driven by the hepatocyte-specific TBG promoter, led to long-term improvement of ALGS liver phenotypes upon one injection at postnatal day 1 (P1). An AAV8 injection at P15, when the liver damage response is activated, also led to phenotypic improvement. CONCLUSIONS: Our preclinical studies provide proof of principle for AAV-mediated Sox4 knockdown in TBG+ cells as a therapeutic approach for ALGS liver disease.
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