Taysha IPO Presentation Deck

Approaches to create a miRNA target panel for regulating MeCP2 expression High-throughput screening of mouse CNS miRNAs upregulated after MeCP2 gene therapy overdose Identify endogenous miRNA targets that are conserved across species and appear frequently among the UTRS of dose-sensitive genes regulating intellectual ability Use positive results from high-throughput screening to filter and rank bioinformatics data Merged screening data and genomic sequence information Create a small synthetic (and potentially broadly applicable) regulatory panel T Regl miRARE High-throughout milNA screen harvest ACTORS CNS CNS RNA Expression for 1900 NA -RTT-speofic panel for top 3 futs Selection criteria to process UTR and create universa panag 38-01 How to use HTS expression data to process UTR sequence doto Sert targets from o UTR dota set according to the expression levot of their cognate mRNAs Torgets for miRNAs expressed in CNS are physiologely relevant and should be priorited for panel design Use pst date to select on expression threshald Eminata sorgets for mRNA expressed below this threshold Eminate targets for fute peative Nita that signently then use positives from HTS select dasase relevant targets from a short list of frequently Tully unique seed sequences aming peative hits (o single sead sequence can appear in mory ndogenous targets appear frequently among 3 UTRs of 12 dose-sensitive genes expressed in brain An Sorted data reveais a relationship between target frequency and tissue-specific expression of miRNAs VALLEY FRAME Amba FALLT WUND 2431 hugs To create a feedbock pen miRNAsxpressed noor injection site Frequency ered by uancy To make the panel broadly applicable select targets that appear in most of the selected UTR FELT WERK To maximize repression, p select torgets for 22 argets Then, to ensure success in a RTT model prioritize targets for h MANAS torgets that may y bind multiple MaCP2-driven mRNAs torgataected for 50

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