Biomedical subjects

Christian Thirion

Publications and source records attributed to Christian Thirion.

2 recordsLinked to original sources

PubMed2025

AAV6 vectors provide superior gene transfer compared to AAV9 vectors following intramyocardial administration.

Cardiac gene therapy using adeno-associated viral (AAV) vectors holds great promise for treating heart diseases but would benefit from more potent AAV vectors. Vectors based on the AAV serotypes 6 and 9 have been used in pre-clinical gene therapy studies, yet the therapeutic outcomes varied depending on the experimental model and delivery route used. Here, we evaluated the transduction efficiency of AAV6, AAV9, and AAV9-derived MyoAAVs for local cardiac delivery. Vectors were tested in neonatal rat ventricular myocytes, and subsequently in mouse hearts by direct intramyocardial injection. Vector genome levels, mRNA expression levels, and fluorescence were measured. The AAV6 and AAV9 vectors were further validated in porcine hearts, human-induced pluripotent stem-cell-derived cardiomyocytes, and human atrial myocardial slices. In both rat cardiomyocytes and mouse hearts, AAV6 exhibited the highest transduction efficiency. Direct comparison of the AAV6 and AAV9 vectors in porcine and human models confirmed that AAV6 is more potent. In conclusion, AAV6 vectors are superior to AAV9 and its derivative vectors for cardiac transduction by direct intramyocardial injection. In addition, the in vivo transduction efficiency correlates with in vitro and ex vivo assays, thereby facilitating the development of more potent AAV variants for cardio-selective delivery methods.

AAV vector↗

PubMed2025

Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library.

Recombinant adeno-associated viruses (AAVs) are leading vectors for in vivo human gene therapy. An integral vector element is promoters, which control transgene expression in either a ubiquitous or cell-type-selective manner. Identifying optimal capsid-promoter combinations is challenging, especially when considering on- versus off-target expression. Here, we report a pipeline for in vivo promoter biopanning in AAV building on our AAV capsid barcoding technology and illustrate its potential by screening 53 promoters in 16 murine tissues using an AAV9 vector. Surprisingly, the 2.2-kb human glial fibrillary acidic protein (GFAP) promoter was the top hit in the liver, where it outperformed robust benchmarks such as the human α-1-antitrypsin promoter or the clinically used liver-specific promoter 1 (LP1). Analysis of hepatic cell populations revealed preferred GFAP promoter activity in hepatocytes. Notably, the GFAP promoter also surpassed the LP1 and cytomegalovirus promoters in human hepatocytes engrafted in an immune-deficient mouse. These findings establish the GFAP promoter as an exciting alternative for research and clinical applications requiring efficient and specific transgene expression in hepatocytes. Our pipeline expands the arsenal of technologies for high-throughput in vivo screening of viral vector components and is compatible with capsid barcoding, facilitating the combinatorial interrogation of complex AAV libraries.

Dependovirus↗