Research and Development Projects Adopted in FY2015

Development of siRNA conjugates with tissue-specific delivery functions

Project Leader:Ueno Yoshihito

Professor, Graduate School of Applied Biological Sciences, Gifu University

Ueno Yoshihito

Small interfering RNAs (siRNAs) have considerable potential as therapeutic drugs for intractable diseases such as cancer because they can be rationally designed and synthesized if the sequences of disease-causing genes are known. However, several barriers exist in the therapeutic application of siRNAs. Unmodified siRNA is easily degraded by nucleases existing either inside or outside cells, does not readily cross membranes to enter cells, and can stimulate the innate immune system. Development of an effective drug delivery system (DDS) to deliver siRNAs to the target tissues is also one of the critical issues in therapeutic application of siRNAs.

In this project, to overcome the above problems, we will create chemically modified siRNAs that are resistant to nucleases. Furthermore, to impart DDS functions to these siRNAs, we will create siRNA conjugates with tissue-specific delivery functions by covalently conjugating the siRNAs with ligands for receptors overexpressed on cancer cell surfaces.

Human RecQL1 DNA helicase (RecQL1) participates in DNA repair and recombination pathways during cell cycle replication and is highly up-regulated in rapidly growing cells, including various cancers and transformed cells. Furuich and co-workers in GeneCare Research Institute Co., Ltd. found that the silencing of the RecQL1 expression by RecQL1-siRNA induces mitotic catastrophe and mitotic cell death but does not affect the growth of normal cells. In this project, we will carry out the study using RecQL1-siRNA as the lead siRNA drug candidate.

In addition, behavior and localization of the siRNA conjugates in the living systems will be analyzed by positron emission tomography (PET) using siRNAs labeled with 11C by the rapid C-[11C]methylation reactions in the National Center for Geriatrics and Gerontology (NCGG).

<Figure1>Project organization diagram

This project will be carried out by a representative research institution (Gifu University) and two other research institutes (GeneCare Research Institute Co., Ltd and National Center for Geriatrics and Gerontology).

<Figure2>Summary of this project

In this project, we aim to create nuclease-resistant siRNAs with DDS functions by conjugating ligands for receptors overexpressed on cancer cell surfaces as pilot molecules.