 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Feb 05, 2024 |
| Title |
Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis |
| Organism |
Macaca mulatta |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebral spinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease.We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453).Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1×1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3×1013 GC/animal) was well tolerated (36–37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9’s proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2+ CNS malignancies.
|
| |
|
| Overall design |
Two adult female rhesus macaques were dosed ICM with 3x10^13 GC of AAV9.UbC.trastuzumab and brain tissue was collected at necropsy 36-37 days post-dosing. scRNA-seq was used to determine cell types that were positive for transgene expression in cerebellum and occitital cortex.
|
| Web link |
https://www.nature.com/articles/s41417-024-00751-1
|
| |
|
| Contributor(s) |
Werner MS, Aras S, Morgan AR, Roamer J, Param NJ, Olagbegi K, Lamontagne RJ, Greig JA, Wilson JM |
| Citation(s) |
38480976 |
| |
| Submission date |
Feb 04, 2024 |
| Last update date |
Mar 14, 2024 |
| Contact name |
James M Wilson |
| Organization name |
University of Pennsylvania
|
| Street address |
125S 31st St
|
| City |
Philadelphia |
| State/province |
Pennsylvania |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
|
| Platforms (1) |
|
| Samples (4)
|
|
| Relations |
| BioProject |
PRJNA1073255 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE255027_RAW.tar |
429.3 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
|
|
|
|
 |
Less...
More...