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Research Review No. 85. Exciting new Developments with Viral Vectors. A recent review. Introduction: It has been known for some time that Adeno-associated viruses (AAV) can be used as a means to transport genetic material into cell, i.e. act as genetic vectors. In the three recent studies, which I am discussing today these vectors are being developed further with promising results for the Duchenne community. As the authors (2) of one of the studies being discussed state in their introduction: “Wild-type AAV is nonpathogenic and recombinant AAV vector is weakly immunogenic Further, AAV is the only gene transfer vector that can effectively transduce all striated muscles in the body in small and large mammals”. Nevertheless, despite all these advantages, they note that there is a major hurdle for the creation of AAV-vector based therapy for the treatment of Duchenne Muscular Dystrophy (DMD). This is the great size of the Dystrophin gene, whose coding sequence is about 11.2kb (kilobases), while the packaging capacity of the AAV is only 5kb. While there have been some studies trying to reduce the size of the Dystrophin to create a so-called mini-dystrophin, which will be able to carry out some of the functions of the a full-length gene, this Holy Grail of gene therapy with regard to replacing the complete functional gene may well be a significant stage nearer. Until full length dystrophin can be produced, we should stil look at the possibility of treating DMD with increasing (up-regulating) the production of Utrophin, as a substitute for dystrophin. As this study (3) also uses AAV-vectors, I thought it useful to add it to the review. The Studies: A study from the U.K., reported earlier this year (1), on similar investigations. They based their study on the fact that recombinant AAV (rAAV) are very attractive potential vectors for DMD gene therapy. They based their studies on the principle of trans-splicing or recombination based overlapping of AAV vectors. The basis of the method is that two independent AAV vectors each of which carries parts of a gene to be incorporated are supplied with appropriate splice signals or with overlapping sequence elements such that they link in only the desired way like are independently packaged in separate AAV vectors. Single appropriate cells are simultaneously infected and thereby one full-length messenger RNA (mRNA) is produced by head-to-tail intermolecular recombination between two independent genomes. This is transcribed in the coinfected cells. However, the problem with DMD is that due to the size of the dystrophin gene, three parts have to be successfully incorporated, hence the phrase ‘Triple Trans-Splicing’ has been coined for this procedure. In their paper (1), which fully described the details of the complex technology, the authors demonstrate the principle that ‘triple trans-splicing vectors have the potential to overcome the size limitation of AAV vector vehicles for the delivery of large genes’. They note that no other data on this concept have been published and they note that they are currently aiming to optimize the design of these triple trans-splicing vectors further so that the ‘splicing between the three vectors is more efficient and expression of the dystrophin protein is enhanced’. In the study, from U.S.A., which has just been published (2) their results suggest that triple trans-splicing AAV vectors can between them expand the total carrying capacity of the AAV vectors to 15 kb, which is more than is essential for the transcription of the dysptophin gene. They consider this as a significant advance in human gene therapy. In their final sentence of their summary they state ‘Further optimization of the trivector strategy may expand the utility of AAV for human gene therapy’, which is a positive sign for the future treatment of DMD. The study (3), from Italy, the authors developed an artificial transcription factor, which goes under the name: “Jazz”. It up-regulates both the human and the mouse utrophin promoter. They had observed a significant recovery of muscle strength in dystrophic Jazz-transgenic mdx mice, a well-known model for human DMD. In their study, they demonstrate the efficacy of an experimental gene therapy based on the systemic delivery of Jazz gene in mdx mice by AAV and they consider that this combination of the techniques “can open a new avenue to obtain a therapeutic strategy for treatment of DMD. References: 1. Koo, T., Popplewell, L., Athanasopoulos, T. & Dickson, G. (2014) Triple Trans-Splicing Adeno-Associated Virus Vectors Capable of Transferring the Coding Sequence for Full-Length Dystrophin Protein into Dystrophic Mice. Human Gene Therapy. 25(2):98-108. 2. Lostal, W., Kodippili, K., Yue, Y.P. & Duan, D.S. (2014) Full-Length Dystrophin Reconstitution with Adeno-Associated Viral Vectors. Human Gene Therapy. 25(6):552-562. 3. Strimpakos, G., Corbi, N., Pisani, C., Di Certo, M.G., Onori, A., Luvisetto, S., Severini, C., Gabanella, F., Monaco, L., Mattei, E. & Passananti, C. (2014) Novel Adeno-Associated Viral Vector Delivering the Utrophin Gene Regulator Jazz Counteracts Dystrophic Pathology in mdx Mice. Journal of Cellular Physiology. 229(9):1283-1291. Karl A. Bettelheim 21.7.2014