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LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy

Ze Wang1, Jiahao Wu2, Zhengyuan Lv1

  • 1School of Basic Medical Sciences, Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.

Journal of Advanced Research
|January 19, 2025
PubMed

Insights

Genetic variants in LMNA cause heart disease, including LMNA-related cardiomyopathy, which is difficult to treat. Gene therapy offers promising new treatment options for this condition.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Medicine

Background:

  • Genetic variants in the LMNA gene are linked to various heart diseases.
  • LMNA-related cardiomyopathy presents with high penetrance and early onset, leading to heart failure or lethal arrhythmias.
  • This condition, a subtype of dilated and arrhythmogenic cardiomyopathy, is resistant to current cardiac therapies, highlighting a significant unmet clinical need.

Purpose of the Study:

  • To provide a comprehensive summary of the genetic basis, disease models, and pathological mechanisms of LMNA-related cardiomyopathy.
  • To highlight recent translational studies and emerging therapeutic strategies for LMNA-related cardiomyopathy.
  • To discuss the potential of gene therapy as a breakthrough treatment for this genetic cardiac disease.

Main Methods:

  • Comprehensive literature review of genetic variants, disease models, and pathological mechanisms.
  • Analysis of recent translational studies focusing on therapeutic modalities.
  • Evaluation of gene therapy approaches including gene supplementation, silencing, and genome editing.

Main Results:

  • LMNA-related cardiomyopathy involves diverse disease mechanisms, challenging traditional small-molecule drug development.
  • A recent first-in-human clinical trial reported futility, underscoring the limitations of current approaches.
  • Gene therapy presents a novel therapeutic avenue by directly targeting LMNA variants.

Conclusions:

  • Gene therapy, including gene supplementation, silencing, and genome editing, offers significant potential for treating LMNA-related cardiomyopathy.
  • The complexity of LMNA-related cardiomyopathy necessitates innovative therapeutic strategies beyond conventional drug development.
  • The principles discussed are applicable to other genetic diseases lacking effective treatments.
Abstract

Keywords:
Disease modelGene therapyGenetic variantLMNA-related cardiomyopathyPathological mechanism

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