Precise gene editing of pathogenic Lamin A mutations corrects cardiac disease

Area of Science:

• Molecular Biology
• Genetics
• Cardiology
• Neuromuscular Diseases

Background:

• Laminopathies are severe genetic disorders caused by mutations in the Lamin A (LMNA) gene, often lacking effective treatments.
• Specific LMNA mutations, L35P and R249Q, lead to congenital muscular dystrophy (CMD) and dilated cardiomyopathy with conduction defects (DCM-CD), respectively.
• Existing cellular and animal models exhibit significant pathological phenotypes mirroring human diseases.

Purpose of the Study:

• To develop and evaluate precise base editing (BE) strategies for correcting pathogenic LMNA gene variants.
• To assess the therapeutic efficacy of base editing in disease models of laminopathies.
• To investigate base editing as a potential treatment for LMNA-related cardiac and muscular diseases.

Main Methods:

• Development of adenine base editing (ABE) for R249Q and cytosine base editing (CBE) for L35P LMNA mutations.
• Utilized induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and humanized mouse models carrying LMNA mutations.
• Adeno-associated virus (AAV) vectors were employed for in vivo delivery of base editing components.

Main Results:

• Base editing corrected LMNA mutations in iPSC-CMs, rescuing in vitro cellular abnormalities like nuclear aberrations and DNA damage.
• In humanized mouse models, AAV-mediated base editing prevented pathological phenotypes, including cardiac dysfunction and muscle-wasting, and extended lifespan.
• ABE and CBE strategies demonstrated high efficacy in correcting pathogenic LMNA variants and ameliorating disease manifestations.

Conclusions:

• Precise base editing is a highly effective strategy for correcting disease-causing LMNA mutations.
• Base editing therapies successfully rescued phenotypes in both cellular and in vivo models of laminopathies.
• This study establishes base editing as a promising therapeutic avenue for treating human laminopathies.