Bag3 P209L myopathies and efficacy of blocking signaling pathways with the therapeutic peptide, MMI-0100
Background and Hypothesis: The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which play a critical role in cellular processes, including protein degradation and turnover. Over 30 Bag3 mutations have been identified, including a Proline209Leucine (P209L) missense mutation which causes a severe childhood cardiomyopathy. The mechanism by which Bag3 mutations causes cardiomyopathy is currently unknown, but the p38/MAPK signaling cascade has been shown to be altered in our animal model that coexpresses the human Bag3 P209L gene. We hypothesized the cellpermeant peptide, MMI-0100, which is known to inhibit MAPK-activated protein kinase 2 (MK2) activity in the p38/MAPK signaling cascade, would alleviate or reduce cardiac dysfunction.
Experimental Design: Echocardiographic analysis of cardiac function of cardiac-specific Bag3 P209L transgenic (and wildtype littermate control) mice (20 – 22 months of age) was assessed by high-resolution ultrasound echocardiography (VisualSonics Vevo 2100, MS550D probe, cardiology package) to document the established disease-related cardiac dysfunction at baseline. Mice were then treated with 100µg/kg/day MMI-0100 nebulized daily for 30 days. Follow-up echocardiography was performed at 10, 20, and 30 days of MMI-0100 treatment. Echocardiographic analysis was performed to determine the systolic function (EF%, FS%), chamber dimensions, and wall thickness in systole and diastole using Vevo 2100 Workstation software package.
Results: Blinded analysis of echocardiographic data identified that Bag3 P209L Tg+ mice had a baseline cardiac dysfunction compared to wildtype controls at 20 months of age (WT= 76% EF, 44% FS; Tg+= 66% EF, 36% FS). MMI-0100 treatment significantly attenuated this dysfunction by 20 days of MMI-0100 treatment (WT= 79% EF, 47% FS; Tg+= 80% EF, 48% FS), consistent with demonstrating for the first time MK2’s role in mediating p38 signaling in the pathogenesis of Bag3 P209L cardiomyopathy.
Conclusion and Potential Impact: The MMI-0100 peptide has proven efficacious in several animal models of fibrosis driven by p38 signaling, as MK2 is a p38 downstream mediator. Future studies seek to translate the use of the MMI-0100 peptide in pediatric patients with Bag3 P209L cardiomyopathy through compassionate use FDA pathways.
Copyright (c) 2019 Ashley R. Hacker, Jessica M. Berthiaume, Monte S. Willis
This work is licensed under a Creative Commons Attribution 4.0 International License.