Plakophillin-2 gene therapy methods and compositions
Inventors
YANG, Zhihong Jane • HO, Jaclyn • Reid, Chris • Yang, Jin
Assignees
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Publication Number
US-11781156-B2
Publication Date
2023-10-10
Expiration Date
Abstract
Provided herein are methods and compositions for plakophilin-2 gene therapy for treating heart diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM).
Core Innovation
The invention relates to gene therapy for arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM) in a mammal, using a viral vector composition that encodes plakophilin 2 (PKP2). The viral vector comprises a nucleic acid sequence at least 90% identical to SEQ ID NO: 2 encoding a PKP2 polypeptide having the amino acid sequence of SEQ ID NO: 8, operatively linked to a cardiac specific promoter and a 3′ element, together with a pharmaceutically acceptable carrier or excipient.
The background problem addressed is desmosome dysfunction in ARVC/ACM, including the loss of PKP2 and associated desmosome structure/function defects that contribute to clinical manifestations. The document describes that desmosomes, including PKP and PKG, are important for cell adhesion, and that PKP2 depletion in iPSC-derived cardiomyocytes results in loss of desmosome protein (DSP) membrane localization and DSP loss.
The invention targets reversal, reduction, or prevention of desmosome dysfunction and clinical manifestations of ARVC/ACM by expressing PKP2 in cardiac tissue. The described approaches also include adeno-associated virus (AAV), including AAV6, AAV8, AAV9, and AAV9 derivatives, and expression cassette constraints tied to sequence identity thresholds and size ranges.
Claims Coverage
The document includes one independent claim covering a PKP2 gene-therapy method for ARVC or ACM in a mammal, with main inventive features centered on administration of a viral vector encoding PKP2 under cardiac-specific transcriptional control and a 3′ element, plus a pharmaceutically acceptable carrier or excipient. Dependent claims refine the independent claim by narrowing viral vector type/serotype, sequence identity threshold, patient selection based on desmosome protein variations, and the specific cardiac or clinical conditions to reverse or reduce.
Cardiac gene transfer encoding PKP2 under cardiac specific promoter and 3′ element
A method for treating ARVC or ACM in a mammal by administering a composition comprising a viral vector with a nucleic acid sequence at least 90% identical to SEQ ID NO: 2 encoding a PKP2 polypeptide having the amino acid sequence of SEQ ID NO: 8 operatively linked to a cardiac specific promoter and a 3′ element, together with a pharmaceutically acceptable carrier or excipient.
Permissible viral vector classes for PKP2 delivery
The method uses a viral vector selected from adeno-associated virus, adenovirus, lentivirus, pox virus, vaccinia virus, or herpes virus.
AAV selection narrowed to specific serotypes/subtypes
The method uses an adeno-associated virus selected from AAV6, AAV8, AAV9, or AAV.rh74.
Sequence identity threshold relative to SEQ ID NO: 2
The method includes using a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 2.
Patient selection based on desmosome protein variation
The method further specifies identifying a mammal as having at least one variation in a desmosome protein.
Reversal or reduction of enumerated ARVC/ACM clinical targets
The method is further defined to reverse or reduce at least one specified cardiac or related clinical condition, including fibrofatty tissue replacement, myocardial atrophy, predominant right ventricular dilation, ventricular arrhythmias, sudden cardiac death, exercise-triggered cardiac events, right ventricular cardiomyopathy, dilation, heart failure, left ventricular cardiomyopathy, atrial arrhythmias, syncope, palpitations, shortness of breath, and chest pain.
Overall claim coverage focuses on administering a viral vector composition encoding PKP2 (SEQ ID NO: 8) under a cardiac specific promoter with a 3′ element to treat ARVC or ACM, with refinements that narrow viral vector classes and AAV serotypes, impose sequence identity thresholds, incorporate desmosome protein-variation based patient selection, and specify cardiac/clinical targets for reversal or reduction.
Stated Advantages
Reverses or reduces ARVC/ACM-associated cardiac or related clinical conditions, including fibrofatty tissue replacement, myocardial atrophy, ventricular arrhythmias, and sudden cardiac death.
Documented Applications
Treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM) in a mammal by administering a PKP2-encoding viral vector composition under cardiac-specific promoter control with a 3′ element.
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