Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy.

Familial dilated cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, dilated cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPβ signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of dilated cardiomyopathy. Displacement of PP2A from mAKAPβ, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPβ-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing dilated cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo . Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in dilated cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for dilated cardiomyopathy.
Competing Interests: M.S.K. and J.L. are inventors of patent-protected intellectual property concerning the targeting of mAKAPβ-PP2A signalosomes to treat heart failure, by which they and Stanford University may gain royalties from future commercialization. M.S.K. holds equity in Cardiac RSK3 Inhibitors, LLC, that has licenses for these therapies.
(© 2024 The Author(s).)