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Development and commercialisation of polyfunctional pyridinium derivatives as potential gene delivery agents

In order to find new efficient and safe agents for gene delivery, the goal is to develop and produce already synthesized and designed novel charged amphiphiles on the basis of pyridinium derivates.

Gene therapy has emerged as an innovative ingredient in medical treatment in the 21st century. Gene therapy could be used to treat both inherited genetic disorders, and effectively correct other pathological processes caused by viral infections or immune system dysfunctions. Moreover, gene therapy could find applications in the early stages of oncological diseases, as well as cardiovascular and neurodegenerative diseases. There are three main types of gene transfections in use, i.e., viral, non-viral (or chemical or cationic amphiphile) and physical. However, the use of viral vectors has some negative aspects - unpredictable mutagenicity of viral vectors, the reaction of the organism's immune system and also technical problems in large-scale production of viral vectors. Other transfection techniques using physical methods, i.e., injection and electroporation, are still too complicated for routine use in medical practice. Taking into account the above mentioned aspects, recent years have seen the use of non-viral gene delivery agents increase rapidly. Such agents are usually synthetic compounds (cationic lipids, polymers) that are able to use complex DNA in liposomes and introduce it into the target cell. The synthetic compounds are preferable for large-scale production, more stable, and furthermore are not immunogenic in general. A wide range of such synthetic cationic amphiphiles is described in literature. The derivatives of pyridinium have also been suggested as transfection agents. Unfortunately, the effectiveness of non-viral gene delivery agents is still insufficient in comparison to viral vectors. Through long experience in their specific areas, scientists at the LATVIAN INSTITUTE OF ORGANIC SYNTHESIS and the UNIVERSITY OF KUOPIO discovered new groups of gene transfection agents: amphiphilic 1,4-dihydropyridine (1,4-DHP) derivatives comprising lipid type substituents and cationic parts. Discovered compounds are protected by a patent application (Pat.WO 01/63946 A1). A double charged compound possessing two dodecyl chains is more effective than DOTAP and PEI 25, widely used gene delivery standards. The synthesized compounds also have several characteristic features which make them different from the known gene transfer agents. Positive properties of 1,4-DHP amphiphiles include: - fluorescent properties allowing investigations of cellular localisation; - prototropy and buffering properties, so fine tuning of the best agents can be achieved in different gene transfer steps; - possibility of comprehensive derivatisation; - it is possible to derivatise the compounds for cellular targeting. Aim of the work: 1. To create a sustainable common scientific - industrial complex comprising specialised complementary scientific laboratories and private enterprises in order to market innovative products - agents for gene transfection (in general - for DNA delivery) as tools for scientific studies and for perspective large-scale industrial production of gene transfection agents for medicinal practice. 2. To develop and upscale the synthesis of target molecules. 3. To generate target oriented synthesis and obtain more superior gene transfection agents by optimising their efficiency, notably steps of cell and membrane penetration. The above mentioned positive properties of the novel group will be used to create more appropriate gene transfection agents. Keywords: gene delivery agents, pyridinium.
Project ID: 
3 371
Start date: 
01-01-2005
Project Duration: 
53months
Project costs: 
70 000.00€
Technological Area: 
Gene - DNA Therapy
Market Area: 
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