Modular Multifunctional Protein Vectors for Gene Therapy

The introduction of genes into the organism or the regulation of the expression of endogenous genes has emerged in the last decade as a very potent strategy for correcting monogenic inherited diseases, treating acute disorders, and slowing down the progression of diseases without known cure. In addition it constitutes an important tool for research, which has been widely used and has contributed to show the mechanisms behind several physiological processes and pathologies. Adequate carriers able to transfer DNA or RNA into target cells have been largely explored. However, this is an area under continuous expansion as there is no ideal vector suitable for all applications. In fact, no individual vector will meet all the characteristics for a perfect or ideal vector, as many of the needs are different and even contradictory. For example, immunogenicity is in most cases an undesirable side effect, while it is a valuable property when treating tumours as it contributes to their clearance. Another example of contradictory needs of one single vector would be the capacity of a vector to determine the overexpression of the transgenic protein for life. This would be an essential property for the treatment of inherited diseases produced by the lack of a particular protein, however for the treatment of acute injuries the lifelong expression of a therapeutic protein will probably be deleterious. Moreover, some vectors do not transduce post-mitotic cells like neurons or muscle fibres, which is a drawback for targeting these cell types but may be an advantage for the targeting of cancer cells. Thus, there is a need for diverse type of vectors for diverse therapeutic or experimental paradigms, and in particular versatile tuneable vectors would be very interesting. Moreover, several basic problems with the known vectors persist, like toxicity, oncogenicity, immunogenicity, low transfection efficiency, or poor bioavailability, which need further consideration and efforts. Due to their natural efficiency, viruses have been modified to act as vectors, and they have shown a good degree of success. Non-viral vectors have also been developed by combining several properties necessary for transfection: nucleic acid attachment and condensation, cell attachment, cell entry, endosomal escape, intracellular trafficking, nuclear entry, and nucleic acid release. Some of these vectors are quite simple, as the ones formed by the combination of nucleic acids and lipid components or other carriers like polyethylene glycol (PEG). Others include the previous components but have in addition attached targeting molecules like antibodies, enabling these vectors to preferentially transfect a given tissue. In fact even