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

Area of Science:

• Cardiovascular Biology
• Gene Therapy
• Molecular Cardiology

Background:

• Familial dilated cardiomyopathy (DCM) is a major cause of heart failure and cardiac transplantation.
• Pathological cardiac remodeling in DCM is linked to protein phosphatase 2A (PP2A) activity at cardiomyocyte perinuclear mAKAPβ signalosomes.
• Current therapies for DCM offer limited efficacy, highlighting the need for novel treatment strategies.

Purpose of the Study:

• To investigate whether disrupting PP2A anchoring to mAKAPβ can prevent DCM-associated cardiac dysfunction.
• To evaluate the therapeutic potential of AAV9sc.PBD gene therapy in a mouse model of familial DCM.

Main Methods:

• Development of an adeno-associated virus gene therapy vector (AAV9sc.PBD) to deliver a PP2A binding domain peptide to cardiomyocytes.
• Utilizing a transgenic mouse model expressing a mutant α-tropomyosin E54K (Tpm1) allele to mimic familial DCM.
• Assessing cardiac structure, function, cardiomyocyte morphology, and gene expression in treated and control mice.

Main Results:

• AAV9sc.PBD administration significantly improved cardiac structure and function in the mutant Tpm1 DCM mouse model.
• The gene therapy vector demonstrated no adverse effects on cardiac parameters in normal, non-transgenic mice.
• At the cellular level, AAV9sc.PBD treatment restored cardiomyocyte morphology and normalized gene expression in the DCM mouse model.

Conclusions:

• Disrupting PP2A anchoring via AAV9sc.PBD is a viable strategy for preventing and treating DCM-associated cardiac dysfunction.
• The findings support AAV9sc.PBD as a potential broad-based therapeutic agent for dilated cardiomyopathy, irrespective of the specific genetic cause.
• Further clinical investigation of AAV9sc.PBD for DCM treatment is warranted based on this proof-of-concept study.