Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis.
Marcela S WernerShweta ArasAshleigh R MorganJillian RoamerNesteene J ParamKanyin OlagbegiR Jason LamontagneJenny A GreigJames M WilsonPublished in: Cancer gene therapy (2024)
Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebrospinal 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 × 10 11 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 × 10 13 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.
Keyphrases
- gene therapy
- epidermal growth factor receptor
- cerebrospinal fluid
- tyrosine kinase
- poor prognosis
- advanced non small cell lung cancer
- resting state
- mass spectrometry
- white matter
- metastatic breast cancer
- liquid chromatography
- functional connectivity
- blood brain barrier
- cerebral ischemia
- binding protein
- gas chromatography
- real time pcr
- dna methylation
- long non coding rna
- rheumatoid arthritis
- single cell
- breast cancer cells
- signaling pathway
- cell cycle arrest
- disease activity