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Updated: Oct 25, 2025
Adeno-Associated Virus-Mediated Delivery of CRISPR for Cardiac Gene Editing in Mice
Published on: August 2, 2018
Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy
Ruth Jinfen Chai1, Hendrikje Werner1, Peter Yiqing Li2
1Skin Research Institute (SRIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Abstract:
Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3-4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1's function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.
Insights
Mutations in LaminA cause dilated cardiomyopathy. Disrupting SUN1 protein function in mice with these mutations significantly extends lifespan and prevents heart failure, offering a potential therapeutic strategy.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cell Biology
Background:
- Mutations in the LaminA gene are a primary cause of monogenic dilated cardiomyopathy.
- LMNA mutations lead to cardiac failure and premature death in affected mice.
Purpose of the Study:
- To investigate the role of the LINC complex protein SUN1 in LaminA-deficient cardiomyopathy.
- To explore the therapeutic potential of disrupting SUN1 function in treating LMNA-related heart disease.
Main Methods:
- Generated mice with cardiomyocyte-specific Lmna deletion.
- Induced Lmna mutations in mice genetically deficient in SUN1.
- Expressed a dominant-negative SUN1 miniprotein in Lmna-deficient cardiomyocytes using Adeno Associated Viral Vector 9.
Main Results:
- Mice with cardiomyocyte-specific Lmna deletion died within 3-4 weeks.
- Genetic deficiency or dominant-negative inhibition of SUN1 extended lifespan in Lmna-mutant mice to over one year.
- SUN1 miniprotein expression prevented cardiomyopathy progression and extended lifespan fivefold by disrupting LINC complex interactions.
Conclusions:
- SUN1 is a critical mediator in LaminA-related cardiomyopathy.
- Targeting SUN1 function offers a promising therapeutic avenue for LMNA-induced dilated cardiomyopathy, potentially bypassing the need for mutation-specific treatments.
