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Exosome-mediated delivery of RNA and DNA for gene therapy.

ABSTRACT: Gene therapy promises to revolutionize biomedicine and personalized medicine by modulating or compensating the expression of abnormal genes. The biggest obstacle for clinical application is the lack of an effective, non-immunogenic delivery system. We show that bovine colostrum exosomes and polyethyleneimine matrix (EPM) delivers short interfering RNA (siRNA) or plasmid DNA (pDNA) for effective gene therapy. KRAS, a therapeutic focus for many cancers, was targeted by EPM-delivered KRAS siRNA (siKRAS) and inhibited lung tumor growth (>70%) and reduced KRAS expression (50%-80%). Aberrant p53 is another therapeutic focus for many cancers. EPM-mediated introduction of wild-type (WT) p53 pDNA (pcDNA-p53) resulted in p53 expression in p53-null H1299 cells in culture, subcutaneous lung tumor, and tissues of p53-knockout mice. Additionally, chemo-sensitizing effects of paclitaxel were restored by exogenous WT p53 in lung cancer cells. Together, this novel EPM technology represents an effective 'platform' for delivery of therapeutic nucleic acids to treat human disease.

SUBMITTER: Munagala R

PROVIDER: S-EPMC8005491 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Exosome-mediated delivery of RNA and DNA for gene therapy.

Munagala Radha R Aqil Farrukh F Jeyabalan Jeyaprakash J Kandimalla Raghuram R Wallen Margaret M Tyagi Neha N Wilcher Sarah S Yan Jun J Schultz David J DJ Spencer Wendy W Gupta Ramesh C RC

Cancer letters 20210218

Gene therapy promises to revolutionize biomedicine and personalized medicine by modulating or compensating the expression of abnormal genes. The biggest obstacle for clinical application is the lack of an effective, non-immunogenic delivery system. We show that bovine colostrum exosomes and polyethyleneimine matrix (EPM) delivers short interfering RNA (siRNA) or plasmid DNA (pDNA) for effective gene therapy. KRAS, a therapeutic focus for many cancers, was targeted by EPM-delivered KRAS siRNA (si ...[more]

PMID: 33610731

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Project description:Bladder cancer (BCa) is one of the most common malignancies affecting men. Oncogenic transcription factors function as an important regulator in the progression of human cancer. In our study, we aimed to construct artificial circular non-coding RNAs (acircRNAs) consisting of three functional units that mimic the CRISPR-Cas system and elucidate its therapeutic role in bladder cancer. Additionally, the compare of the efficiency in regulating gene expression between acircRNA and CRISPR-dCas systems was performed. We connected the cDNA sequences of TFs aptamer and constructed a circRNA. To demonstrate the platform's practicality, β-catenin and NF-κB were chosen as functional targets, while T24 and 5637 cell lines served as test models. Real-time Quantitative PCR (qPCR), double luciferase assay and related phenotype assay were used to detect the expression of related genes and the therapeutic effect. To elucidate the functionality of acircRNAs, luciferase vectors capable of detecting β-catenin and NF-κB expression were employed to assess the inhibitory impact of acircRNA on β-catenin and NF-κB. Consequently, the optimal combination involving acircRNA-3 was determined. Next, qPCR assay was employed to assess the relative expression levels of target downstream genes following acircRNA treatment. The expression of c-myc and cyclin D1 were used to determine the function of β-catenin, while Bcl-XL and TRAF1 were used to determine that of NF-κB. The acircRNAs inhibited the β-catenin and NF-κB related signaling in BCa cells specifically. CD63-HuR fusion protein was used to loading acircRNA into exosomes. The results showed that acircRNA could inhibit the activity of the target transcription factors, and the inhibitory effect was better than that of CRIPSR-dCas9-KRAB. Furthermore, functional experiments demonstrated that the transfection of acircRNA in bladder cells resulted in decreased proliferation, enhanced apoptosis, and suppressed migration. In conclusion, our synthetic gene device exhibited anti-tumor regulatory capabilities and showed greater efficiency in tumor suppression compared to the CRISPR-dCas9-KRAB system. Therefore, our device provides a new strategy for cancer treatment and could be a useful strategy for cancer cells.

Dataset Information

Exosome-mediated delivery of RNA and DNA for gene therapy.

Publications

Exosome-mediated delivery of RNA and DNA for gene therapy.

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