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An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy
Pengfei Gu1, Jie Zhao2, Wei Zhang1
1Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Abstract:
Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR-dCas9 in targeting AURKA or KDM1A and improving disease-specific prognosis and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA-triggered CRISPR-dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.
Insights
This study engineered a synthetic gene circuit combining oleanolic acid (OA) and CRISPR-dCas9 to target cancer genes, rapidly treating lung and thyroid cancers synergistically.
Area of Science:
- Oncology
- Synthetic Biology
- Gene Therapy
Background:
- Cancer pharmacotherapies are limited, especially for rare diseases.
- Oleanolic acid (OA), a plant-derived compound, has therapeutic potential.
- CRISPR-dCas9 offers targeted gene regulation for therapeutic applications.
Purpose of the Study:
- To engineer a synthetic gene circuit for synergistic cancer treatment.
- To combine oleanolic acid (OA) with CRISPR-dCas9 targeting.
- To investigate the therapeutic potential against AURKA or KDM1A in cancer.
Main Methods:
- Utilized a synthetic-biology-inspired design principle.
- Engineered an OA-triggered CRISPR-dCas9 transcriptional repression system.
- Applied the system to target AURKA or KDM1A in cancer models.
Main Results:
- The engineered gene circuit rapidly and simultaneously attenuated lung and thyroid cancer.
- Demonstrated synergistic therapeutic effects by multiplexing targeting efficiencies.
- Showcased the potential of OA and CRISPR-dCas9 in a combined therapeutic strategy.
Conclusions:
- Rationally engineered synthetic gene circuits can treat multifactorial diseases synergistically.
- This approach enhances therapeutic efficacy by combining drug actions.
- Highlights a novel strategy for improving cancer treatment outcomes.
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