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| 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
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| 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.
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| Overall design |
Mice were injected with rAAV packaged with the KP1 capsid, nuclei were isolated, and Cut&Tag analysis was performed
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| Web link |
https://www.sciencedirect.com/science/article/pii/S152500162400306X?via%3Dihub
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| Contributor(s) |
Pekrun K, Stephens CJ, Gonzalez-Sandoval A, Goswami A, Zhang F, Tarantal AF, Blouse G, Kay MA |
| Citation(s) |
38715361 |
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| Submission date |
Mar 06, 2024 |
| Last update date |
Jun 10, 2024 |
| Contact name |
Katja Pekrun |
| E-mail(s) |
kpekrun@stanford.edu
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| Organization name |
Stanford School of Medicine
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| Department |
Pediatrics & Genetics
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| Lab |
CCSR 2110
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| Street address |
269 Campus Drive
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| City |
STANFORD |
| State/province |
CA |
| ZIP/Postal code |
94025 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| 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 |
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| Relations |
| BioProject |
PRJNA1084875 |
