DNA Therapeutics

Évry, France

DNA Therapeutics

Évry, France

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Patent
Dna Therapeutics, Institute Curie and French National Center for Scientific Research | Date: 2017-03-01

The present invention relates to an optimized in vivo delivery system with endosomolytic agents for nucleic acid of therapeutic interest conjugated to molecules facilitating endocytosis, in particular for use in the treatment of cancer.


Dutreix M.,Institute Curie Hospital | Cosset J.M.,University Pierre and Marie Curie | Sun J.-S.,DNA Therapeutics | Sun J.-S.,French Natural History Museum
Mutation Research - Reviews in Mutation Research | Year: 2010

Approximately half of all cancer patients are treated with radiation therapy. However, some tumor cells can escape the lethal effects of irradiation by hypoxia, deregulation of the cell cycle or apoptosis or by increasing their ability to repair the DNA damage induced, resulting in recurrence of disease. In order to overcome these resistance mechanisms, various strategies have been developed. Over the last decade, extensive progress in human genomics and genetic tools has been made. Several methods using DNA or RNA molecules have been developed to target angiogenesis or other cellular functions in order to restore sensitivity to irradiation. In this review, we focus on five classes of nucleic acid-based approaches, (i) gene transfer by recombinant plasmid or virus, (ii) immune-stimulating oligonucleotides, (iii) antisense oligonucleotides, (iv) siRNA and shRNA, and (v) siDNA (signal interfering DNA), which target specific proteins or pathways involved in radioresistance. We review the results of the preclinical studies and clinical trials conducted to date by combining nucleic acid-based molecular therapy and radiotherapy. © 2010 Elsevier B.V. All rights reserved.


Devun F.,Institute Curie | Biau J.,Institute Curie | Biau J.,Center Jean Perrin | Huerre M.,Institute Curie | And 10 more authors.
Radiology | Year: 2014

Purpose: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer. Materials and Methods: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm3, mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences. Results: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors. Conclusion: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy. © 2014 RSNA.


Patent
Dna Therapeutics, French National Center for Scientific Research and Institute Curie | Date: 2011-06-21

The present invention relates to an optimized in vivo delivery system with endosomolytic agents for nucleic acid of therapeutic interest conjugated to molecules facilitating endocytosis, in particular for use in the treatment of cancer.


Patent
Dna Therapeutics, Institute Curie and French National Center for Scientific Research | Date: 2015-10-27

The present invention relates to an optimized in vivo delivery system with endosomolytic agents for nucleic acid of therapeutic interest conjugated to molecules facilitating endocytosis, in particular for use in the treatment of cancer.


Patent
Dna Therapeutics, Institute Curie and French National Center for Scientific Research | Date: 2016-08-10

The present invention relates to an optimized in vivo delivery system with endosomolytic agents for nucleic acid of therapeutic interest conjugated to molecules facilitating endocytosis, in particular for use in the treatment of cancer.


Patent
Dna Therapeutics and Institute Curie | Date: 2012-05-25

The present invention relates to a method for treating a cancer including a combination of a treatment by a nucleic acid molecule mimicking double strand breaks with hyperthermia.


Solass W.,Otto Von Guericke University of Magdeburg | Herbette A.,Institute Curie | Schwarz T.,Reger Medizintechnik | Hetzel A.,Reger Medizintechnik | And 5 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2012

Background: Peritoneal carcinomatosis is an unmet medical need. Laparoscopy offers a unique opportunity to control and to steer the operating environment during surgery by loading carbon dioxide with a therapeutic substance and creating the so-called therapeutic capnoperitoneum. We have treated a human sample of peritoneal carcinomatosis from an endometrial adenocarcinoma ex vivo just after surgery. Methods: A nontoxic therapeutic agent (Dbait) was aerosolized into a box containing diseased human peritoneum under a pressure of 12 mmHg CO2. Dbait (noncoding DNA fragments) acts through jamming DNA damage sensing and signaling, ultimately inhibiting DNA repair system of cancer cells. Dbait were coupled to cholesterol molecules to facilitate intracellular uptake, and to Cyanine (Cy5) to allow detection by fluorescence. In a control experiment, the same solution was applied to the other half of the sample using conventional lavage. Results: Physical results revealed fluorescence within the tumor up to 1 mm depth in the therapeutic capnoperitoneum sample and no uptake in the lavage sample. Biological results showed intranuclear phosphorylation of H2AX in the nebulized sample and no activity in the lavage sample. Importantly, tumor nodules showed more activity than the neighbor, normal peritoneum. Detection of histone gamma-H2AX (phosphorylated H2AX) reveals activation of DNA-dependent protein kinase (DNA-PK) by Dbait, which has been shown to be the key step for sensitization to genotoxic therapy. Conclusions: Dbait are taken up by cancer cells and have a biological activity up to 1 mm depth. Nebulization of the molecule is significantly more effective than conventional lavage. This proof of principle supports the need for clinical studies applying therapeutic capnoperitoneum together with Dbait for treating peritoneal carcinomatosis. © 2011 The Author(s).


Patent
Institute Curie and Dna Therapeutics | Date: 2012-11-28

The present invention relates to a method for treating a cancer including a combination of a treatment by a nucleic acid molecule mimicking double strand breaks with hyperthermia.


PubMed | Otto Von Guericke University of Magdeburg, Ruhr University Bochum, Institute Curie and DNA Therapeutics
Type: Journal Article | Journal: Endoscopy | Year: 2016

A novel therapeutic concept, pressurized intraluminal aerosol chemotherapy (PILAC), and a corresponding device for distributing drugs to the mucosa and submucosa of the distal esophagus are presented.The endoscopic device that was designed consisted of (i) a double-balloon catheter, similar to a Sengstaken-Blakemore tube; (ii) a carbon dioxide (CO2) line, used to create a gaseous, pressurized environment; and (iii) a micropump, used to generate a therapeutic aerosol. The device was inserted into the distal esophagus in three narcotized Landrace pigs. Dbait (short interfering DNA, or siDNA) was aerosolized under pressure (12mmHg) in CO2 at 37C for 30 minutes.The procedure was well tolerated by all animals. At autopsy, no mucosal or muscular tear was observed. Fluorescence microscopy revealed a homogeneous intramural distribution of Dbait-cyanine 5 in the esophageal wall down to the circular muscular layer (400-600m).PILAC is feasible in a large animal model and appears to be safe. Therapy of the entire tissue at risk for the development of cancer in the distal esophagus is possible without the prior endoscopic identification of diseased tissue.

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