{"id":6110,"date":"2021-10-16T17:15:51","date_gmt":"2021-10-16T06:15:51","guid":{"rendered":"https:\/\/rettaustralia.org.au\/?p=6110"},"modified":"2021-10-16T17:38:11","modified_gmt":"2021-10-16T06:38:11","slug":"a-game-changer-for-gene-therapy-for-rett-syndrome","status":"publish","type":"post","link":"https:\/\/rettaustralia.org.au\/blog\/a-game-changer-for-gene-therapy-for-rett-syndrome\/","title":{"rendered":"A GAME CHANGER FOR GENE THERAPY FOR RETT SYNDROME."},"content":{"rendered":"
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As noted in previous articles now on the RSAA website, gene therapy for Rett Syndrome represents a potential cure. Other potential strategies are being explored but gene therapy probably represents the strategy most likely to reach the clinic first. Many of these strategies use an adeno-associated virus (AAV) to deliver the MeCP2 gene to neurons in the brain.<\/p>\n
Several issues still need to be overcome:<\/p>\n
This raises the probability that MeCP2 will be over-expressed in neurons which contain a functional MeCP2 gene, in turn leading to the possibility of MeCP2 duplication syndrome.<\/p>\n
Years of research have failed to overcome the dilemma of MeCP2 over-expression<\/u> leading to MeCP2 duplication syndrome versus MeCP2 under-expression<\/u> resulting in no change in the behaviour of mice with Rett Syndrome. In a recent landmark study, a strategy to control the level of MeCP2 expression and thus avoid MeCP2 duplication syndrome was recently described in a paper from Professor Steven Gray’s laboratory in the University of Texas, Dallas (Sinnett SE et al, 2021. Engineered microRNA-based regulatory element permits safe high-dose miniMeCP2 gene therapy in Rett mice. Brain <\/em>May 5;awab182. doi: 10.1093\/brain\/awab182<\/em>).<\/p>\n MicroRNA (miRNA) is another type of RNA produced in a cell and recognises messenger RNA (mRNA-the intermediate template molecule that results in production of a protein). The miRNA binds to mRNA resulting in loss of expression of the protein. Professor Gray’s team hypothesized that it should be possible to find a miRNA that can bind to MeCP2-specific mRNA and thus inhibit MeCP2 expression.<\/p>\n Professor Gray and his team identified several miRNA molecules which were expressed in cells as a by-product of MeCP2 over-expression. These miRNA molecules recognise an independent target which was termed a m<\/u>iRNA-R<\/u>esponsive A<\/u>uto-R<\/u>egulatory E<\/u>lement (miRARE), “a built-in inhibitory element responsive to MeCP2 overexpression”.<\/p>\n The use of a miniMeCP2 gene freed up space in the recombinant AAV-MeCP2 genome to permit the inclusion of the miRARE element. Thus, after delivery of the AAV-MeCP2-miRARE to neurons in mice, only neurons which contained the defective MeCP2 protein were shown to express the truncated (functional) MeCP2 protein encoded by the miniMeCP2 gene and resulted in significant improvement in the Rett severity scores. The principle of the process is explained in Figure 1.<\/p>\n <\/p>\n FIGURE 1<\/strong><\/p>\n <\/p>\n <\/p>\nWhat is the immediate impact of this research?<\/strong><\/h4>\n