Tumour suppression by targeted intravenous non-viral CRISPRa using dendritic polymers

Kretzmann, Jessica A.; Evans, Cameron W.; Moses, Colette; Sorolla, Anabel; Kretzmann, Amy L.; Wang, Edina; Ho, Diwei; Hackett, Mark J.; Dessauvagie, Benjamin F.; Smith, Nicole M.; Redfern, Andrew; Waryah, Charlene Babra; Nörret, Marck; Iyer, K. Swaminathan; Blancafort, Pilar

doi:10.1039/c9sc01432b

Cited by 40 publications

(43 citation statements)

References 47 publications

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“…To enhance cancer cell selectivity, we generated a bifunctional melittin peptide by engineering an N-terminal alpha-helical RGD peptide motif (RGD1-melittin, derived from TGF-β3, sequence HGRGDLGRLKK), which interacts with αvβ6 and αvβ3 integrins overexpressed on breast cancer cell membranes and tumor-associated vasculature 44 – 46 . When engineered with bioactive peptides, RGD motifs enhance targeting to breast cancer cells 47 . The IC 50 of RGD1-melittin was not significantly different compared to parental melittin in T11 cells, indicating that the potency was not affected by the RGD motif (Fig.…”

Section: Resultsmentioning

confidence: 99%

Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

et al. 2020

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Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee (Apis mellifera) venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. Honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast carcinoma cells. Mutational studies reveal that a positively charged C-terminal melittin sequence mediates plasma membrane interaction and anticancer activity. Engineering of an RGD motif further enhances targeting of melittin to malignant cells with minimal toxicity to normal cells. Lastly, administration of melittin enhances the effect of docetaxel in suppressing breast tumor growth in an allograft model. Our work unveils a molecular mechanism underpinning the anticancer selectivity of melittin, and outlines treatment strategies to target aggressive breast cancers.

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Section: Resultsmentioning

confidence: 99%

Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

et al. 2020

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“…The use of cyclic RGD-functionalized dendritic polymers has enabled targeted activation of TSGs via SpdCas9-VPR in a mouse model of breast cancer. A long-lasting therapeutic effect with negligible tissue toxicity was achieved after intravenous injection of the plasmid DNA polyplex ( 255 ). Furthermore, sufficient levels of endogenous tumor suppressor miR-524 upregulation have been achieved in a mouse model of triple-negative breast cancer to result in a therapeutic effect.…”

Section: Targeted Delivery Systems For Dcas9-mediated Epigenome Editimentioning

confidence: 99%

Epigenome engineering: new technologies for precision medicine

Sgro

Blancafort

2020

Nucleic Acids Research

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Chromatin adopts different configurations that are regulated by reversible covalent modifications, referred to as epigenetic marks. Epigenetic inhibitors have been approved for clinical use to restore epigenetic aberrations that result in silencing of tumor-suppressor genes, oncogene addictions, and enhancement of immune responses. However, these drugs suffer from major limitations, such as a lack of locus selectivity and potential toxicities. Technological advances have opened a new era of precision molecular medicine to reprogram cellular physiology. The locus-specificity of CRISPR/dCas9/12a to manipulate the epigenome is rapidly becoming a highly promising strategy for personalized medicine. This review focuses on new state-of-the-art epigenome editing approaches to modify the epigenome of neoplasms and other disease models towards a more ‘normal-like state’, having characteristics of normal tissue counterparts. We highlight biomolecular engineering methodologies to assemble, regulate, and deliver multiple epigenetic effectors that maximize the longevity of the therapeutic effect, and we discuss limitations of the platforms such as targeting efficiency and intracellular delivery for future clinical applications.

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“…Use of CRISPRa systems resulted in increased gene expression that led to phenotypic changes in the mice, including mouse models of diabetes, muscular dystrophy, and acute kidney disease [262]. Recently, delivery of dCas9-VP64 targeted down-regulated genes in breast cancer resulted in increased gene expression and reduction in tumor growth in mouse xenografts [263]. Viral-based delivery of dCas9-VP64 has also been demonstrated to overcome haploinsufficiency in two obese mouse models.…”

Section: Crispr-mediated Activation Of Gene Expressionmentioning

confidence: 99%

Gene editing and CRISPR in the clinic: current and future perspectives

et al. 2020

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Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases which require cell modification in vivo. However, in vivo use of CRISPR technologies can be confounded by problems such as off-target editing, inefficient or off-target delivery, and stimulation of counterproductive immune responses. Current research addressing these issues may provide new opportunities for use of CRISPR in the clinical space. In this review, we examine the current status and scientific basis of clinical trials featuring ZFNs, TALENs, and CRISPR-based genome editing, the known limitations of CRISPR use in humans, and the rapidly developing CRISPR engineering space that should lay the groundwork for further translation to clinical application.

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Tumour suppression by targeted intravenous non-viral CRISPRa using dendritic polymers

Abstract: This article demonstrates a fully synthetic strategy enabling CRISPR-mediated activation of tumour suppressor genes in vivo to reduce tumour burden.

Cited by 40 publications

References 47 publications

Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

Epigenome engineering: new technologies for precision medicine

Gene editing and CRISPR in the clinic: current and future perspectives

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