BX-120 Smith - Strömberg Generation of biologically active nanocomplexes
Project Summary: Objectives, expected results, summary of the Project plan
Objectives: The objective is to develop a new form of safe, efficient and well-defined gene delivery technology with great future clinical potential. Since such a technology does not exist, this is a major challenge with high risk, but also high potential return, since it could change the way genes are delivered into people. Expected results: The development of a gene transfer technology, where functional entities, providing all the functions needed for efficient gene delivery, are positioned in such a way that this nanocomplex is biologically active. It is a prerequisite that the delivery system works in vivo, since there are multiple experimental systems, which only work in tissue cultures.
Summary of the project plan: We will address several key issues. (1) Generation of improved hybridization anchors by new chemistry, thereby increasing sequence selectivity, as well as to glue functional entities, such as ligands for cell surface receptors, to the nanocomplex. (2) Optimization of "functional entity- linker" pairs to provide accessibility of the functional entity, e.g. hybridized nuclear localizing signal peptides that are freely movable in three dimensions. (3) Development of chemistry to include non-Watson-Crick recognition elements as well as encircled anchors, which will provide strong hybridization in spite of low molecular weight. (4) Improvement of the efficacy in an iterative fashion (novel composition chemistry -> three-dimensional structure analysis -> in vivo delivery -> novel composition chemistry etc.) using gene transfer into muscles and liver. (5) Apart from plasmid-based delivery we will also develop transfer systems for RNA silencing (siRNAs).
Keywords for the project (to be found in international databases)
Plasmid, RNAi, gene therapy, peptide-nucleic-acid, modified oligonucleotides