AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans

Chantal J M van Opbergen; Bitha Narayanan; Chester B Sacramento; Katie M Stiles; Vartika Mishra; Esther Frenk; David Ricks; Grace Chen; Mingliang Zhang; Paul Yarabe; Jonathan Schwartz; Mario Delmar; Chris D Herzog; Marina Cerrone

doi:10.1161/CIRCGEN.123.004305

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans

Chantal J M van Opbergen
, Bitha Narayanan
, Chester B Sacramento
, Katie M Stiles
, Vartika Mishra
, Esther Frenk
, David Ricks
, Grace Chen
, Mingliang Zhang
, Paul Yarabe
, Jonathan Schwartz
, Mario Delmar
, Chris D Herzog
, Marina Cerrone

Research output: Contribution to journal › Article › Academic › peer-review

10 Downloads (Pure)

Abstract

BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.

METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.

RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.

CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.

Original language	English
Pages (from-to)	e004305
Journal	Circulation. Genomic and precision medicine
Volume	17
Issue number	1
DOIs	https://doi.org/10.1161/CIRCGEN.123.004305
Publication status	Published - 1 Feb 2024
Externally published	Yes

Keywords

arrhythmogenic right ventricular cardiomyopathy
cardiomyopathies
death, sudden
genetic therapy
plakophilins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1161/CIRCGEN.123.004305

Aav-mediated-delivery-of-plakophilin-2a-arrests-progression-of-arrhythmogenic-right-ventricular-cardiomyopathy-in-murine.pdfFinal published version, 3.75 MBLicence: CC BY

Cite this

van Opbergen, C. J. M., Narayanan, B., Sacramento, C. B., Stiles, K. M., Mishra, V., Frenk, E., Ricks, D., Chen, G., Zhang, M., Yarabe, P., Schwartz, J., Delmar, M., Herzog, C. D., & Cerrone, M. (2024). AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans. Circulation. Genomic and precision medicine, 17(1), e004305. https://doi.org/10.1161/CIRCGEN.123.004305

@article{1f3f486dbe2f4f33bb2dff467e9b0ef4,

title = "AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans",

abstract = "BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100\% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100\% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.",

keywords = "arrhythmogenic right ventricular cardiomyopathy, cardiomyopathies, death, sudden, genetic therapy, plakophilins",

author = "\{van Opbergen\}, \{Chantal J M\} and Bitha Narayanan and Sacramento, \{Chester B\} and Stiles, \{Katie M\} and Vartika Mishra and Esther Frenk and David Ricks and Grace Chen and Mingliang Zhang and Paul Yarabe and Jonathan Schwartz and Mario Delmar and Herzog, \{Chris D\} and Marina Cerrone",

year = "2024",

month = feb,

day = "1",

doi = "10.1161/CIRCGEN.123.004305",

language = "English",

volume = "17",

pages = "e004305",

journal = "Circulation. Genomic and precision medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "1",

}

van Opbergen, CJM, Narayanan, B, Sacramento, CB, Stiles, KM, Mishra, V, Frenk, E, Ricks, D, Chen, G, Zhang, M, Yarabe, P, Schwartz, J, Delmar, M, Herzog, CD & Cerrone, M 2024, 'AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans', Circulation. Genomic and precision medicine, vol. 17, no. 1, pp. e004305. https://doi.org/10.1161/CIRCGEN.123.004305

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans. / van Opbergen, Chantal J M; Narayanan, Bitha; Sacramento, Chester B et al.
In: Circulation. Genomic and precision medicine, Vol. 17, No. 1, 01.02.2024, p. e004305.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans

AU - van Opbergen, Chantal J M

AU - Narayanan, Bitha

AU - Sacramento, Chester B

AU - Stiles, Katie M

AU - Mishra, Vartika

AU - Frenk, Esther

AU - Ricks, David

AU - Chen, Grace

AU - Zhang, Mingliang

AU - Yarabe, Paul

AU - Schwartz, Jonathan

AU - Delmar, Mario

AU - Herzog, Chris D

AU - Cerrone, Marina

PY - 2024/2/1

Y1 - 2024/2/1

N2 - BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.

AB - BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.

KW - arrhythmogenic right ventricular cardiomyopathy

KW - cardiomyopathies

KW - death, sudden

KW - genetic therapy

KW - plakophilins

UR - https://www.scopus.com/pages/publications/85185289213

U2 - 10.1161/CIRCGEN.123.004305

DO - 10.1161/CIRCGEN.123.004305

M3 - Article

C2 - 38288614

SN - 2574-8300

VL - 17

SP - e004305

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

IS - 1

ER -

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this