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rAAV-based and intraprostatically delivered miR-34a therapeutics for efficient inhibition of prostate cancer progression

Gene Therapy volume 29, pages 418–424 (2022)Cite this article

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Abstract

At present, there is no effective treatment for prostate cancer (PCa). Previous studies have reported that miR-34a is significantly downregulated in PCa cells; therefore, modulation of miR-34a expression might be a promising therapeutic approach for PCa treatment. To this end, we first verified the downregulation of miR-34a in prostate tumors from a transgenic adenocarcinoma mouse prostate (TRAMP) model. We found that miR-34a overexpression significantly inhibited the cell cycle, viability, and migration of PCa cells by targeting its downstream genes. Next, we tested the concept of intraprostatic injection of rAAV9·pri-miR-34a into 8-week-old TRAMP mice to inhibit PCa progression. We observed that the treatment lowered body weights significantly compared to the control treatment starting at 30 weeks after injection. rAAV9·pri-miR-34a treatment also obviously extended the lifespan of TRAMP mice. Moreover, we confirmed that the neoplasia in the treated prostates was significantly diminished compared to that in the control group. In addition, overexpressed miR-34a downregulated the expression of its target genes. Taken together, our results demonstrated, for the first time, the potential of rAAV-mediated efficient modulation of miR-34a expression in the prostate to inhibit PCa progression by regulating its downstream gene expression.

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Fig. 1: miR-34a expression in prostate tumors of TRAMP mice.
Fig. 2: miR-34a overexpression significantly inhibits the PC3 cell cycle in vitro.
Fig. 3: miR-34a overexpression significantly suppresses PC3 cell viability and migration in vitro.
Fig. 4: miR-34a downregulates the expression of CCND1 in PC3 cells.
Fig. 5: rAAV9 effectively and safely transduces normal prostate and PCa cells in vivo.
Fig. 6: miR-34a overexpression improves the survival of TRAMP mice.
Fig. 7: miR-34a overexpression decreases the malignancy of PCa.
Fig. 8: miR-34a overexpression downregulates Ccnd1 gene expression in vivo.

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (81702536, 82070784) to JA, grants from University of Massachusetts Medical School (an internal grant) and National Institutes of Health (R01NS076991-01,1P01AI100263-01, UG3 HL147367-01, 4P01HL131471-02, and R01HL097088) to GG, a grant from Science & Technology Department of Sichuan Province, China (2018HH0153) to JA, and a grant from 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18011) to HL.

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Authors and Affiliations

  1. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China

    Jianzhong Ai, Qiang Wei & Hong Li

  2. Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA

    Jianzhong Ai, Jia Li, Qin Su, Hong Ma, Ran He & Guangping Gao

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  1. Jianzhong Ai
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Correspondence to Jianzhong Ai or Guangping Gao.

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GG is a co-founder of Voyager, Adrenas, and AspA Therapeutics specialized in rAAV-based gene therapy, and holds equity in the companies. GG is an inventor on patents with potential royalties licensed to Voyager, AspA, and other biopharmaceutical companies.

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Ai, J., Li, J., Su, Q. et al. rAAV-based and intraprostatically delivered miR-34a therapeutics for efficient inhibition of prostate cancer progression. Gene Ther 29, 418–424 (2022). https://doi.org/10.1038/s41434-021-00275-5

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