Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — ASGCT 24th Annual Meeting (May 2021)
10 slides from Wave Life Sciences's conference presentation, May 14, 2021
Slide 1: A versatile platform for ADAR-mediated RNA editing in vivo in preclinical models
A versatile platform for ADAR-mediated RNA editing in vivo in preclinical models Prashant Monian Wave Life Sciences Presented at ASGCT 24th Annual Meeting May 14, 2021
Slide 2: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, r
Slide 3: PRISM enables practical approach to RNA editing without need for viruses or exogenous protein
PRISM enables practical approach to RNA editing without need for viruses or exogenous protein Wave ADAR-editing oligonucleotides Alternative Base-Editing Systems Delivery vehicles Genetic construct or foreign protein Extracellular space Intracellular Exogenous ADAR or Endogenous other base editors A
Slide 4: PRISM platform enables rational drug design
PRISM platform enables rational drug design Sequence Chemistry O 5’ B B B: bases R: 2’ modifications O A, T, C, mC, G, U, OMe, MOE, F, - 3’ 2’ other modified bases R other modifications XX O Sequence Chemistry P O O X: backbone chemistry 5’ B Stereochemistry Phosphodiester (PO), O Stereochemistry ph
Slide 5: GalNAc-conjugated and unconjugated oligonucleotides support efficient RNA editing
GalNAc-conjugated and unconjugated oligonucleotides support efficient RNA editing TAG TGG In vivo editing NHP liver Editing in NHP GalNAc conjugate 1-week post-dose (Multiple 5 mpk, SC doses) unconjugated Baseline Post-treatment (45 days) (Single 50 mpk, SC dose) In vitro dose-response GalNAc conjug
Slide 6: Humanized ADAR1 mouse
Humanized ADAR1 mouse Expression in hepatocytes ADAR1 GAPDH • Transgenic mouse expressing human ADAR1 Expression in neurons • Expression of ADAR in liver C57Bl/6 mouse hADAR1 mouse Human and neurons in mouse approximates expression in ADAR1 corresponding human tissues GAPDH Western blots showing exp
Slide 7: Humanized ADAR mouse model editing similar to editing in NHPs
Humanized ADAR mouse model editing similar to editing in NHPs Editing UGP2 in liver Editing UGP2 Editing SRSF1 3-days post-dose 1-week post-dose 1-week post-dose (GalNAc conjugate) (Unconjugated) (Unconjugated) * ** **** ** ** Left: GalNAc-conjugated oligo was administered by SC injection to hADAR m
Slide 8: Oligonucleotides direct editing throughout CNS of hADAR mouse
Oligonucleotides direct editing throughout CNS of hADAR mouse In vitro dose-response curves Editing in CNS of hADAR mouse (Single ICV injection, 100 µg) ACTB UGP2 100 100 80 UGP2 *** *** 80 80 60 PBS *** % Editing % Editing % Editing 60 60 *** 40 40 40 ** ** 20 20 20 0 0 0 0.010.1 1 10 100 0.01 0.1
Slide 9: Wave ADAR editing oligonucleotides are highly specific
Wave ADAR editing oligonucleotides are highly specific RNA editing within ACTB transcript RNA editing within transcriptome (human hepatocytes) (human hepatocytes) C 0% Mock Confidence (LOD score) T 100% ACTB Coverage C 53.8% Editing T 46.2% oligonucleotide Genome coordinates ACTB % Editing Editing s
Slide 10: Summary
Summary • Stereopure oligonucleotides, generated with PRISM, promote RNA editing with endogenous ADAR enzymes in cellular and animal models • GalNAc-conjugated and unconjugated oligonucleotides elicit robust editing in primary hepatocytes and liver of NHP and hADAR mice • There are species-specific
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