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Series GSE261045 Query DataSets for GSE261045
Status Public on Mar 11, 2024
Title Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human Factor IX variant in mice and rhesus macaques (Tn5 mouse)
Organism Mus musculus
Experiment type Other
Summary We investigated long-term human coagulation Factor IX expression of a novel variant when delivered into mice and rhesus macaques and compare transduction efficiencies using two different AAV capsids. In hemophilic mice injected with KP1-packaged rAAV expressing the hyperactive FIX variant specific activity plasma levels were 10-fold or 2-fold enhanced when compared to wild-type or Padua huFIX injected mice, respectively. In rhesus macaques AAV-LK03 capsid outperformed AAV-KP1 in terms of antigen expression and liver transduction. Two animals from each group showed sustained low-level huFIX expression at 3 months post-administration, while one animal from each group lost huFIX mRNA and protein expression over time despite comparable vector copies. We investigated if epigenetic differences in the vector episomes could explain this loss of transcription. Cut&Tag analysis revealed lower levels of activating histone marks in the two animals that lost expression. When comparing rAAV genome associated histone modifications in rhesus macaques to those in mice injected with the same vector, the activating histone marks were starkly reduced in macaque-derived episomes. Differential epigenetic marking of AAV genomes may explain different expression profiles in mice and rhesus macaques as well as the wide dose response variation observed in primates in both preclinical and human clinical trials.
 
Overall design Mice were injected with rAAV packaged with the KP1 capsid, nuclei were isolated, and Cut&Tag analysis was performed
Web link https://www.sciencedirect.com/science/article/pii/S152500162400306X?via%3Dihub
 
Contributor(s) Pekrun K, Stephens CJ, Gonzalez-Sandoval A, Goswami A, Zhang F, Tarantal AF, Blouse G, Kay MA
Citation(s) 38715361
Submission date Mar 06, 2024
Last update date Jun 10, 2024
Contact name Katja Pekrun
E-mail(s) kpekrun@stanford.edu
Organization name Stanford School of Medicine
Department Pediatrics & Genetics
Lab CCSR 2110
Street address 269 Campus Drive
City STANFORD
State/province CA
ZIP/Postal code 94025
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (2)
GSM8133089 R1-M-46-KP
GSM8133090 R1-M-48-KP
This SubSeries is part of SuperSeries:
GSE261047 Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human Factor IX variant in mice and rhesus macaques
Relations
BioProject PRJNA1084875

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Supplementary file Size Download File type/resource
GSE261045_RAW.tar 934.5 Mb (http)(custom) TAR (of BEDGRAPH)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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