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TECHNOLOGY LICENSING OPPORTUNITY

Coding polypurine hairpins for the treatment of cancer
Executive summary
A research group from the University of Barcelona (UB) has developed a new technology able to silence a target gene, based on polypurine hairpins. These hairpins are able to bind to a polypyrimidine target sequence located in the coding strand of a target gene, thus causing a decrease in gene expression. The group is looking for a license, but other collaborations may be considered. polypyrimidine sequences in the template DNA strand. Coding-PPRHs allow the use of this technology to genes where the polypyrimidine sequence is located in the coding DNA strand. Both types of PPRHs show very similar activity.

Advantages
First in vitro results show that PPRHs are superior to siRNA technology:     Low immunogenicity. Up to 4-fold more stable than siRNA Better or equivalent in vitro knocking down activity than siRNA. Easier handling and cheaper synthesis.

Introduction
Hoogsteen bonds play an important role in the mechanism of action of TFOs and circular oligonucleotides, which have been used with great success, but have found some stability and specificity problems. As an attempt to solve these problems, a molecule that binds to its target sequence by WatsonCrick bonds instead of by Hoogsteen bonds has been designed. Polypurine Reverse-Hoogsteen hairpins (PPRH) are non-modified DNA molecules formed by two polypurine stretches linked by a five-thymidine loop. The hairpin structure is maintained by intramolecular Reverse-Hoogsteen bonds between the two polypurine stretches, which are in antiparallel orientation. These molecules bind to their polypyrimidine target sequence by Watson-Crick bonds, thus forming a triplex structure. We have initially described a type of PPRHs with the ability to bind to a target sequence located in the template DNA strand, Template-PPRHs. The formation of the triplex between these PPRHs and their dsDNA target sequence interfered with the transcription process, thus producing an mRNA decrease. In vitro binding studies revealed that Template-PPRHs were able to bind to their dsDNA polypyrimidine target sequence in a sequence specific manner. These PPRHs showed a remarkable stability without containing modified nucleotides. In comparison with other molecules that decrease mRNA levels, TemplatePPRHs showed greater activity than aODNs and similar to that produced by siRNA. The difficulty to design PPRHs resides in finding pure polypyrimidine stretches, but this problem was minimized placing adenines in front of purine interruptions.

Current stage of development
The project is at in vitro stage: 4 targets in advanced clinical trials in Oncology are being analyzed. Several liposomal drug delivery alternatives are under analysis in an in vivo setting in order to start an efficacy in vivo assay by the end of the year.

Goal
The group is looking for a license, but other collaborations may be considered.

Patent
PCT application submitted on April 2011

Reference (AVCRI code)
AVCRI104

Contact
Gemma Hernandez Email: ghernandez@fbg.ub.es

Description
A new type of PPRHs has been developed, CodingPPRHs. These PPRHs directly target the pre-mRNA and the coding strand, thus allowing the application of the PPRH technology to genes whose polypyrimidine sequences are located in the coding DNA strand. Coding-PPRHs extend the application of PPRHs, as the use of Template-PPRHs was limited to the presence of

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