DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer

Gofrit, Ofer N.; Benjamin, Shalva; Halachmi, Sarel; Leibovitch, Ilan; Dotan, Zohar; Lamm, Donald L.; Ehrlich, Nahum; Yutkin, Vladimir; Ben-Am, Monique; Hochberg, Abraham

doi:10.1016/j.juro.2013.12.011

Cited by 94 publications

(62 citation statements)

References 15 publications

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“…Moreover, the use of small molecules can, for example, inhibit the interaction of HOTAIR with LSD1 and PRC2 [92,93]. The therapeutic usage of H19-regulated double-stranded DNA plasmid BC-819 has already been successfully tested in patients with bladder cancer [94]. However, most studies using lncRNAs as therapeutic targets were performed on cell cultures or animal models and only few studies involving human subjects have been carried out.…”

Section: Discussionmentioning

confidence: 99%

Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

Smolle

Bauernhofer

Pummer

et al. 2017

IJMS

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The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread.

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Section: Discussionmentioning

confidence: 99%

Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

Smolle

Bauernhofer

Pummer

et al. 2017

IJMS

View full text Add to dashboard Cite

show abstract

“…For comparison, transfection efficiencies of other conventional DNA-loaded nanocomplexes based on PEI (PEI-CN) and PLL (PLL-CN) were also evaluated. PEI is the most widely explored cationic polymer for gene delivery applications in vitro and in preclinical settings [32], including brain gene transfer studies [33,34], and has been tested in clinical trials for gene therapy of several cancers [35,36]. The PLL-CN used here is composed of DNA condensed into nanocomplexes using block copolymers of a 30-mer PLL connected to PEG via a cysteine residue; this DNA nanocomplex was well tolerated by cystic fibrosis patients [37] and demonstrated promising results in rodent brain [38,39].…”

Section: Resultsmentioning

confidence: 99%

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

Mastorakos

Zhang

Song

et al. 2017

Journal of Controlled Release

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The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain.

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“…Furthermore, since low molecular weight PEI is less toxic than high molecular weight PEI, several groups have developed PEI derivatives capable of degrading into smaller subunits in physiological conditions, such as in aqueous, acidic and/or reducing environments [172–175]. Of note, albeit not for inhaled gene therapy, PEI has been tested in clinical trials for other gene therapy applications [177, 178]. …”

Section: Gene Delivery Platformsmentioning

confidence: 99%

Barriers to inhaled gene therapy of obstructive lung diseases: A review

Kim

Duncan

Hanes

et al. 2016

Journal of Controlled Release

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Knowledge of genetic origins of obstructive lung diseases has made inhaled gene therapy an attractive alternative to the current standards of care that are limited to managing disease symptoms. Initial lung gene therapy clinical trials occurred in the early 1990s following the discovery of the genetic defect responsible for cystic fibrosis (CF), a monogenic disorder. However, despite over two decades of intensive effort, gene therapy has yet to help patients with CF or any other obstructive lung disease. The slow progress is due in part to poor understanding of the biological barriers to inhaled gene therapy. Encouragingly, clinical trials have shown that inhaled gene therapy with various viral vectors and non-viral gene vectors is well tolerated by patients, and continued research has provided valuable lessons and resources that may lead to future success of this therapeutic strategy. In this review, we first introduce representative obstructive lung diseases and examine limitations of currently available therapeutic options. We then review key components for successful execution of inhaled gene therapy, including gene delivery systems, primary physiological barriers and strategies to overcome them, and advances in preclinical disease models with which the most promising systems may be identified for human clinical trials.

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DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer

Abstract: BC-819 prevented new tumor growth in two-thirds of the patients and ablated a third of the marker lesions. Prolonged time to recurrence was observed in responding patients. These results along with the good safety profile make BC-819 a potential medication for bladder cancer.

Cited by 94 publications

References 15 publications

Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

Barriers to inhaled gene therapy of obstructive lung diseases: A review

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