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Prodrug Platform for Rare Colonic Diseases - Rare Diseases 2011

Redaktion

Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.

Kooperation

This project is one of the six winners of the call 2011 «Rare Diseases - New Approaches». Project partner: ETZH

Projektdaten

  • Projekt-Nr: GRS-041/11 
  • Förderbeitrag: CHF 300'000.00 
  • Bewilligung: 01.11.2011 
  • Dauer: 05.2012 - 07.2015 
  • Handlungsfeld:  Rare Diseases, 2009 - 2014

Projektleitung

Projektbeschreibung

Nucleic acids, such as antisense oligonucleotides (AONs) and small interfering RNAs (siRNAs) have enormous potential as therapeutics for life-threatening diseases because in principle, any problematic gene can be targeted with high efficacy and sequence-specificity. However, they suffer from low bioavailability due to their poor permeation characteristics and susceptibility to degradation by nucleases. Chemical modification or analogs of nucleic acids can increase resistance to enzymatic degradation but do not solve the challenges of delivery. Nucleic acids have been conjugated to cell penetrating peptides (CPPs) to enhance their uptake. However, the uptake process is not tissue selective and therefore problematic for applications in humans.

Oral delivery of nucleic acid drugs to the colon would be highly desirable to provide new options for the treatment of serious and rare colonic diseases such as ulcerative colitis, Crohn’s colitis, and Lynch syndrome, but has been challenging due to the harsh conditions found in the gastrointestinal tract and low cellular uptake. In this project, we propose to develop a prodrug platform of a polynucleotide conjugate that will be activated selectively in the colon lumen by bacterial enzymes which are present in the gut flora. This conjugate will be designed to be stable in the upper gastrointestinal tract and deliver locally the nucleic acid drug to the colonic mucosa. This prodrug should constitute a versatile vehicle to explore new therapeutic targets and design more effective drugs in rare bowel diseases.

Was ist das Besondere an diesem Projekt?

The aim of this project is to design a nucleic acid prodrug that is stable in the upper gastrointestinal tract, activated in the colon, and internalized in the colonic mucosa. Until now, «activatable» CPP peptide strategies have only been explored for imaging purposes using proteases overexpressed in tumor tissues as triggers. This research would constitute the first drug delivery application of activatable CPPs. In addition to the formulation design per se, the data stemming this work should provide, in the future, powerful tools to explore the role of various proteins and miRNA involved in the pathology of inflammatory bowel disease or colonic cancer. More importantly, it will allow establishing a technological platform, which could be exploited for the oral treatment of several rare colonic diseases. Treatments based on nucleic acids have, while conceptually promising, failed to meet initial expectations largely because of inadequate delivery to the target site and poor or inefficient cellular uptake. By selecting a locally accessible target (colonic mucosa) and exploiting the particular enzymatic environment of the colonic lumen, a clinically viable delivery system for orally-administered AONs could be realistically developed.

Stand/Resultate

We have identified a suitable CPP-PNA structure for gene silencing and successfully synthesized the corresponding activatable CPP-PNA model prodrug for the local modulation of gene expression in the colon mucosa. We have shown in in vitro experiments that the active antisense structure is restored by reduction of azo-bonds between protective PEG chains and conjugate’s lysine residues. The developed colon specific cleavable PEGylation could be widely applied for the delivery of therapeutic oligonucleotides targeting rare colonic diseases. In the future, we aim at evaluating this technology in an animal model of inflammatory bowel disease through collaborations. In parallel, this research allowed the identification of other local nucleic acid delivery strategies for the treatment of intestinal diseases.

Publikationen

Lee S. H., Moroz E. V., Castagner B. and Leroux J.-C. «Activatable cell penetrating peptide–peptide nucleic acid conjugate via reduction of azobenzene PEG chains». J. Am. Chem. Soc., 2014, 136:12868–12871 (DOI: 10.1021/ja507547w);
Buerkli C.*, Lee S. H.*, Moroz E. V., Stuparu M. C., Leroux J.-C., and Khan A,. «Amphipathic Homopolymers for siRNA delivery: probing impact of bifunctional polymer composition on transfection». Biomacromolecules, 2014, 15:1707–1715 (DOI: 10.1021/bm5001197), *equal contribution;
Lee S. H., Castagner B. and Leroux J.-C. Is there a future for cell-penetrating peptides in oligonucleotide delivery? Eur J Pharm Biopharm. 2013, 85:5-11. (DOI: 10.1016/j.ejpb.2013.03.021);
Moroz E. V., Lee S.H., Jahns H., Hall J., Yamada K., Damha M., Castagner B., Leroux J.-C.. «Amphiphilic nucleic acid conjugates for local treatment of intestinal diseases». 1st European Conference on Pharmaceutics – Drug Delivery, Reims, France, April 13 - 14, 2015. (oral presentation);
Moroz E. V., Lee S. H., Jahns H. I, Hall J., Yamada K., Damha M. J., Castagner B. and Leroux J.-C. «Amphiphilic nucleic acid conjugates for the treatment of colonic diseases». Doktorandentag ETH Zürich, Zurich, Switzerland, September 10, 2014. (oral presentation);
Lee S. H.; Moroz E.; Castagner B.; Leroux, J.-C. «Cell Penetrating Peptide-Peptide Nucleic Acid (CPPPNA) Conjugates for Inflammatory Bowel Disease Therapy» International Congress on Research of Rare and Orphan Diseases - RE(ACT) Congress, Basel, Switzerland, 5-8 March 2014. (poster);
Moroz E. V., Lee S. H., Yamada K., Damha M. J., Castagner B. and Leroux J.-C. «Amphiphilic Nucleic Acid Conjugates for Local Treatment of Colonic Diseases» 10th International Conference and Workshop on Biological Barriers, Saarbrücken, Germany, 16-21 February 2014. (poster);
Lee S. H.; Castagner B.; Leroux, J.-C. «Synthesis of Cell Penetrating Peptide-Peptide Nucleic Acid (CPPPNA) Conjugates and Evaluation of their Biological Performance» Swiss Chemical Society Fall Meeting,Lausanne, Switzerland, 6 September 2013. (poster);
Moroz E., Yamada K., Deleavey G., Damha M. J., Lee S. H., Castagner B., Leroux J.-C. «Chemically Modified Nucleic Acid Conjugates for Local Delivery to the Colon» Swiss Pharma Science Day, Bern, Switzerland, 28 August 2013. (poster);
Moroz E., Yamada K.; Deleavey G., Damha M. J., Lee S. H., Castagner B. and Leroux J.-C. «Amphiphilic Antisense Oligonucleotides for Local Delivery to the Colon» Pharma Posterday, Zürich, Switzerland, 20 August 2013. (poster);
Moroz E.V., Dr. Lee S.H., Dr. Castagner B., Prof. Leroux J.-C. «Colon-specific Delivery of Nucleic Acid Drugs via Oral Administration» Rare Diseases Summer School, Wädenswil, Switzerland, 4-6 July 2013. (poster).

Medienecho

None so far

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Am Projekt beteiligte Personen

Letzte Aktualisierung dieser Projektdarstellung  16.07.2018