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Antisense gene therapy of brain cancer with an artificial virus gene delivery system
Yun Zhang1, Chunni Zhu, William M Pardridge
1Department of Medicine, UCLA School of Medicine, Los Angeles, California 90024, USA.
Abstract:
Therapeutic genes are delivered to the nuclear compartment of cancer cells following intravenous administration with a non-immunogenic "artificial virus" gene delivery system that uses receptor-specific monoclonal antibodies (MAb) to navigate the biological barriers between the blood and the nucleus of the cancer cell. Mice implanted with intracranial U87 human glial brain tumors are treated with a nonviral expression plasmid encoding antisense mRNA against the human epidermal growth factor receptor gene (EGFR). The plasmid DNA is packaged within the interior of polyethylene glycol-modified (PEGylated) immunoliposomes, and delivered to the brain tumor with MAbs that target the mouse transferrin receptor (TRFR) and the human insulin receptor (INSR). The mouse TRFR MAb enables transport across the tumor vasculature, which is of mouse brain origin, and the INSR MAb causes transport across the plasma membrane and the nuclear membrane of the human brain cancer cell. The lifespan of the mice treated weekly with an intravenous administration of the EGFR antisense gene therapy packaged within the artificial virus is increased 100% relative to mice treated either with a luciferase gene or with saline.
Insights
This study demonstrates a novel artificial virus for gene therapy, successfully delivering therapeutic genes to brain tumors and doubling lifespan in mice. This breakthrough offers new hope for brain cancer treatment.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Intravenous gene delivery to brain tumors faces significant biological barriers.
- Targeted delivery systems are crucial for effective cancer gene therapy.
Purpose of the Study:
- To develop and evaluate a non-immunogenic artificial virus for targeted gene delivery to intracranial brain tumors.
- To assess the efficacy of EGFR antisense gene therapy delivered via this system in a mouse model.
Main Methods:
- Utilized PEGylated immunoliposomes encapsulating an EGFR antisense gene plasmid.
- Employed dual-targeting monoclonal antibodies (MAbs) against mouse transferrin receptor (TRFR) and human insulin receptor (INSR).
- Administered the gene therapy intravenously to mice with U87 human glial brain tumors.
Main Results:
- The artificial virus successfully delivered therapeutic genes to the nucleus of cancer cells.
- TRFR MAb facilitated tumor vasculature transport, while INSR MAb enabled cell and nuclear membrane crossing.
- Weekly intravenous administration resulted in a 100% increase in lifespan compared to control groups.
Conclusions:
- The developed artificial virus system is effective for targeted gene delivery across biological barriers.
- EGFR antisense gene therapy shows significant therapeutic potential for brain tumors.
- This approach offers a promising strategy for enhancing brain cancer treatment outcomes.