遺伝子治療とＤＤＳ 遺伝子デリバリーとバイオマテリアル

Abstract

Though number of fundamental and clinical studies of gene therapy offered its exciting potential in treating human diseases, several issues such as non-specific immune reaction owing to viral vectors were pointed out. Therefore, increasing demand will be placed on the development of non-viral vectors. The most commonly examined synthetic carriers are based on cationic polymer/DNA complexes or cationic lipid/DNA complexes. However, the insufficient efficacy and toxicity of these delivery systems limited their applications to therapeutic uses. For improving potentiality of the non-viral vector, considerable efforts are recently paid in designing tailor-made biomaterials. Such materials may allow genes and genetic materials i) to be delivered to specific tissues and cells, ii) to be translocated to particular compartment, i.e. cytosol or nucleus, in the cells, and iii) to exhibit enhanced functionality at the site of action. Unsatisfactory collidal stability and non-specific interaction of the complex with proteins and cells resulted in massive uptake of the complex by non-target tissues including reticuloendotherial systems (RES) and interfered with cell-specific delivery. Modification of cationic polymers or lipids with water-soluble polymers, such as poly(ethylene glycol) (PEG) and polysaccharides, has been employed to overcome these shortcoming. Such soluble carriers are further conjugated with cell-specific ligands to increase cell uptake or provide cell-specificity. To facilitate cytosolic delivery of DNA, various peptides or polymers that perturb plasma or endosomal membrane are utilized. Nuclear localizing signal which helps translocation of macromolecules from cytosol to nucleus through nuclear pores was also conjugated to DNA or carrier systems to control final destination. Insufficient binding affinity of oligonucleotides (ODN) with target molecules would be another reason why ODN medicine on the basis of antisense and antigene strategy can not take effects as it expected. Efforts to increase hybridization opportunity of ODN medicine with its target molecules using tailor-made biomaterials are also described in this review.