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Antisense oligonucleotide therapy for calmodulinopathy

ABSTRACT: Antisense oligonucleotide therapy for calmodulinopathy

PROVIDER: PRJNA1030420 | ENA |

REPOSITORIES: ENA

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Antisense oligonucleotide therapy for calmodulinopathy

Project description:Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant gain of function variants in one of three genes, CALM1, CALM2, and CALM3, which each encode the identical calmodulin (CaM) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, while the other two calmodulin genes would preserve CaM level and function. Here we tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) and mouse models of CALM1 pathogenic variants. Human CALM1F142L/+ iPSC-CMs exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization of CALM1F142L/+ iPSC-CMs. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced arrhythmia in CalmN98S/+ mice without causing observable toxicity. These results provide proof-of-concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.

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Project description:Next generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. We compared intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in good and poor productive uptake tumour cells, PC9 and LK2 respectively. We found that the majority of AZD4785 is rapidly delivered to CD63+ late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+ LE in PC9 but not in LK2 cells. Moreover, both cells recycle AZD4785 in the extracellular vesicles (EVs) however AZD4785 quantification by advanced mass spectrometry and proteomic analysis revealed that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhanced AZD4785 activity in LK2 but not in PC9 cells thus offering novel strategy to possibly enhance ASO potency in poor productive uptake tumour cells.

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