Fig. 8: Optimized construct outperforms published construct in late-stage Mybpc3-/- mice. | Nature Communications

Fig. 8: Optimized construct outperforms published construct in late-stage Mybpc3-/- mice.

From: AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models

Fig. 8

a Homozygous mice with advanced disease (2.5 months of age) were injected retro-orbitally with 3E13 vg/kg or 1E14 vg/kg of AAV9 vector encoding Mybpc3 in the context of the published 5.4 kb cassette (denoted “Published”) or the TN-201 mouse surrogate (AAV9:mMybpc3, denoted mTN-201), or injected with vehicle control. Both cassettes utilize sequence from the human cardiac troponin T (TNNT2) promoter. b EF was measured to represent contractile ability at 27 weeks post-delivery. c LV mass was measured to represent hypertrophy and was normalized to body weight at 27 weeks post-delivery. WT (n = 8; 4 M/4 F), Mybpc3-/- Veh (n = 7; 3 M/4 F), Mybpc3-/- mTN-201 3E13 (n = 6; 2 M/4 F), Mybpc3-/- Published 3E13 (n = 7; 4 M/3 F), Mybpc3-/- mTN-201 1E14 (n = 7; 4 M/3 F), and Mybpc3-/- Published 1E14 (n = 6; 4 M/2 F). d Sustained cardiac transduction 20-months post-injection drove e sustained cardiac Mybpc3 RNA at ~4× levels of endogenous transcript and sustained restoration of wild-type protein levels in dosed homozygotes 20-months post-injection. MYBPC3 protein expression was assessed by ELISA with equivalent total protein for each sample, as well as immunoblot analysis of equivalent total protein, with MYBPC3 intensities normalized to WT (f, representative blot). n = 11 mice/group; 4 M/7 F for WT and 6 M/5 F for mMybpc3. P-value per one-way ANOVA with Tukey’s multiple comparisons test. Error bar: mean ± Standard Error of the Mean (SEM). Source data are provided as a Source Data file.

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