Data demonstrate that SynITRs elicit tissue-specific transduction enhancement and alter the cellular stress response and offer an alternative context to elucidate wtITR biology for targeted, enhanced, and potentially safer human gene therapy.
Evidence that cell-type-specific promoters lose fidelity when paired with neurogenic transgene payloads and that published in vivo reprogramming efficiencies may be substantially confounded by promoter leakage in the absence of formal lineage tracing are synthesized.
M. Abdelnaby, A. Galiakberova, E. Dashinimaev· International Journal of Mol...· 0 citations
Background: Adeno-associated virus (AAV) vector-mediated gene transfer is an emerging treatment strategy for severe cardiac disorders with genetic etiology. We refined the AAV toolkit to achieve efficient and selective expression of the therapeutic transgene in mouse hearts. Methods: Using vectors with a reporter transgene, we evaluated AAV administration routes, AAV serotype tropism to the myocardium, and cardiospecific promoters. Results: We showed that systemic AAV administration provides potent delivery and uniform transduction of cardiac tissue, outperforming localized injection techniques. The MyoAAV 2A capsid variant enabled an improved heart-to-liver transduction ratio compared to the parental AAV9 serotype. Screening a panel of cardiac and pan-muscular promoters in vitro and in vivo verified the superiority of the cardiac troponin T (cTnT) promoter for robust heart-specific transgene expression. Finally, we demonstrated that the cumulative properties of systemic AAV delivery, the MyoAAV 2A serotype, and the cTnT promoter allowed for efficient cardiac synthesis of the therapeutic transgene—an artificial miRNA designed for the gene suppression strategy of FLNC-related cardiomyopathy. Conclusions: Our findings establish an effective AAV approach for transgene transfer into the mouse heart and promote the development of gene therapy for cardiac disorders.
I. Galkin, V. Skopenkova, Maria Y. Shubina et al.· BioTech· 0 citations
The data support the genomic safety of rAAV6 and its applicability to hematological gene therapy and functional enrichment analysis indicated associations with general cellular and structural processes, without enrichment in oncogenic pathways.
H. Lee, Nayoung Park, In-Byung Park et al.· International Journal of Ste...· 0 citations
This study generated a novel recombinant AAV vector rAAV.hu.hu.S17, derived from the human spleen isolate AAV.hu.S17, and systematically evaluated its capsid features, in vitro transduction, and in vivo tissue tropism.
Wenyan Guo, Jiawen Sun, Fei Wang et al.· Journal of Genetic Engineeri...· 0 citations
A novel approach to detarget liver transduction is developed by transiently downregulating the expression of key entry factors in this tissue using GalNac-siRNAs prior to AAV9 administration, which blunted hepatic transduction but also redirected the vector to other transduction-permissive tissues.
K. Kubek-Luck, J. Velazquez, Xiao-Rui Yao et al.· Molecular Therapy· 0 citations
Adeno-associated virus (AAV) gene therapy is frequently hindered by dose-limiting toxicities and preexisting neutralizing antibodies (nAbs). Here, we evaluate enhancer polymer (ePL), a cargo-less poly(L-lactic-co-glycolic acid) nanoparticle, the systemic administration of which demonstrated biocompatibility in nonhuman primates (NHPs) and generated a protransduction serum secretome that significantly enhanced AAV uptake in human iPSC-derived cardiomyocytes. Proteomic analysis of human peripheral blood mononuclear cell-derived secretomes identified a transient upregulation of AAV-entry factors, including ITGB3, alongside a downregulation of inflammatory cytokine pathways. Mechanistically, ePL-stimulated macrophages release a paracrine secretome that triggers the rapid, transient degradation of hepatic insulin receptor substrate 2 and subsequent AKT inhibition in liver and isolated primary mouse hepatocytes. Additionally, ePL attenuated the levels of NHP-derived nAbs in vitro and in a mouse-NHP xenotransfusion model without depleting total systemic immunoglobulins. Finally, ePL reduced Immunoglobulin G (IgG) secretory capacity of splenic B cells, suggesting a mechanistic link by which levels of nAbs are likely attenuated. Together, these findings highlight ePL as a promising supporting agent to improve AAV gene transfer, warranting its further optimization for clinical translation.
Lauren Switala, A. Khandaker, Sumita Dutta et al.· Human Gene Therapy· 0 citations
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