BioRxiv. 2023 Jul 18
Yueshen Sun, Congting Guo, Zhan Chen, Junsen Lin, Luzi Yang, Yueyang Zhang, Chenyang Wu, Dongyu Zhao, Blake Jardin, William T. Pu, Mingming Zhao, Erdan Dong, Xiaomin Hu, Shuyang Zhang and Yuxuan Guo
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Research Field: cardiovescular

AAV Serotype: AAV9

Dose: We conducted a serial dilution of the AAV-Lmna-sgRNA vector and injected high (2×10^11), mid (2×10^10) and low (2×10^9) doses of AAV into P1 RosaCas9-Tom mice.

Routes of Administration: subcutaneously

Targeted organ: heart

Animal or cell line strain: RosaCas9-Tom mice


Aims: Recombinant adeno-associated viruses (rAAVs) are federally approved gene delivery vectors for in vivo gene supplementation therapy. Loss-of-function truncating variants of LMNA, the coding gene for Lamin-A/C, are one of the primary causes of inherited dilate cardiomyopathy (DCM). Here we aim to study whether AAV-based LMNA supplementation could treat LMNA deficiency-triggered cardiac defects. Methods and Results: We compared whole-body, cardiomyocyte-specific and genetic-mosaic mouse models that carry Lmna truncating variants at the same genetic loci and uncovered primarily a non-cell autonomous impact of Lmna on cardiomyocyte maturation. Whole-body lamin-A supplementation by rAAVs moderately rescued the cardiac defects in Lmna germline mutants. By contrast, cardiomyocyte-specific lamin-A addback failed to restore the cardiomyocyte growth defects. A Cre-loxP-based AAV vector that expresses lamin-A throughout the body but excluding the heart was able to restore cardiomyocyte growth in Lmna germline mutants. Conclusions: Lmna regulates cardiomyocyte growth non-cell autonomously. Non-myocytes are the key cell targets for a successful gene therapy for LMNA-associated cardiac defects. Translational perspective: LMNA truncating mutations are among the major causes of inherited DCM. AAV gene supplementation therapy is emerging as a promising strategy to treat genetic cardiomyopathy, but whether this strategy is suitable for LMNA cardiomyopathy remained unclear. Our study counterintuitively showed that the cardiomyocytes are not necessarily the correct therapeutic cell targets for AAV-based treatment of LMNA cardiomyopathy. By contrast, careful elucidation of cell-autonomous versus non-cell-autonomous gene functions is essential for the proper design of a gene supplementation therapy for cardiomyopathy.

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