Publisher： Bentham Science Publishers
E-ISSN： 1875-5631|8|5|295-295
ISSN： 1566-5232
Source： Current Gene Therapy, Vol.8, Iss.5, 2008-10, pp. : 295-295
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
Abstract
In the widest sense, gene therapy may be defined as the delivery of nucleic acids to patients for therapeutic purposes. Thus, it involves the deliberate introduction, usually by means of a vector, of nucleic acid sequences into cells of a patient to treat a disease. The DNA sequences introduced into these cells may correspond either to a functional gene encoding a protein of therapeutic interest or to sequences capable of interfering with the functioning of a cellular gene. Gene therapy is actively investigated for the treatment of both genetic and acquired diseases. However, although some positive results have already been reported in the clinical setting, the clinical trials performed to date have highlighted that a crucial requirement for successful gene therapy is the use of an efficient gene delivery system perfectly adapted to the pathological situation. Ideally, these DNA delivery systems should : (i) be safe, non-toxic, non-immunogenic and well tolerated, (ii) protect and compact DNA into small particles ; i.e. below 300 nm in diameter to be compatible with cell internalization, (iii) provide a stealthy behavior in order to improve in vivo bioavailability; i.e. prevent particles removal from the blood by the monophagocytic system allowing to target cells of interest, (iv) penetrate into the target cells and escape from the endosomes, (v) target nucleic acid sequences to the nucleus where the expression of the protein will take place.The future of gene therapy will depend on the ability to provide to DNA delivery systems all the properties listed above. Viruses have been tailored by evolution for transferring their genes from one cell to another. Accordingly, viruses can be viewed as sophisticated nucleic acid containing macromolecular assemblies which are primed for the introduction of nucleic acid sequences into their target cells. However, viral vectors suffer from some inconveniences including immunogenicity, safety issues and practical issues relating to large scale production and quality control. Thus, a major research effort has been dedicated to the development of alternative approaches to recombinant viruses. The main alternatives to viral vectors aims at developing complex “virus-like” systems consisting of direct complexation of naked DNA with chemical nanocarriers capable of bringing the required properties. Indeed, nonviral vectors offer a means to create sophisticated modular self-assembling gene delivery systems incorporating various functional elements to overcome the distinct extracellular and cellular barriers to gene transfection. Thus, this review will focus on current work coming from opposite but complementary sciences; (i) chemistry for the synthesis of nanocarriers, (ii) physicochemistry for the formulation of DNA with nanocarriers, (iii) cellular biology for the extracellular targeting and intracellular trafficking, (iv) molecular biology for the sustained expression of the transgene by its genome integration or using matrix attachment regions, and (v) physiology for the preclinical and clinical evaluation of the transfection efficiency and therapeutic effect. These convergent efforts should lead to the designed of versatile non viral vectors that will be organized at the nanometric scale, which will be enable them to cross efficiently, safely the cell barriers and to be targeted to the site or organ where they will be active, and provide a beneficial effect. Ultimately, this will allow to fill in the existing gap between the huge therapeutic potential of the nucleic acid sequences and their concrete translation to innovative treatments or vaccines.
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