Cardiac delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs) for treating genetic cardiomyopathies.

Genetic cardiomyopathies involving intrinsic abnormalities of the heart, are frequently driven by gain-of-function mutations, producing toxic proteins or mRNAs that contribute to the disease pathogenesis. Treatment typically includes standard of care therapy for heart failure and arrhythmias rather than targeting the underlying genetic cause. Antibody-Oligonucleotide Conjugates (AOCs) offer a novel method to deliver small interfering RNA (siRNA) therapeutics directly to cardiac cells, holding a significant promise for precision medicine in cardiology, particularly for patients affected by gain-of-function mutations.. AOCs can be designed for precision cardiology therapies by reducing the expression of the targeted gene.. To evaluate the delivery and efficacy of AOCs to reduce the expression of targeted mRNA in heart.. We developed AOCs towards mice or non-human primates (NHPs) utilizing anti-TfR1 monoclonal antibodies conjugated to siRNA against the DMPK mRNA via a stable chemical linker. To evaluate the novel AOC platform to deliver siRNA and silence genes in the heart, mice were administered systemic intravenous AOC at 3 mg/kg (siRNA dose), and tissues were evaluated for siRNA concentration and Dmpk mRNA reduction on day 28. To evaluate the translation and tolerability of the AOC in larger species, NHPs were administered systemic intravenous AOC (2, 6 or 45 mg/kg siRNA dose) and tissues were evaluated for siRNA concentration and DMPK mRNA reduction.. A single dose of AOC at 3 mg/kg in mice resulted in approximately 75% reduction of Dmpk mRNA in both the heart and gastrocnemius muscle by day 28. However, no mRNA reduction was observed in the liver, despite similar siRNA concentrations in the liver and gastrocnemius tissues, with cardiac siRNA delivery being about 10 times greater. In NHPs, a single dose of AOC at 6 mg/kg led to significant DMPK mRNA reduction across various striated muscle tissues, including the heart, with no significant reduction observed in non-muscle tissues. A dose-response effect was also observed in cardiac DMPK mRNA reduction in NHPs following 9 months of chronic treatment (2 or 45 mg/kg). Additionally, AOC mediated reduction of DMPK mRNA in NHPs for 9 months was not associated with any adverse effects.. Our data suggests that AOC technology can efficiently deliver siRNA to the heart, significantly reducing the expression of targeted genes. This approach holds great promise as a therapeutic option for a subset of cardiomyopathies due to toxic gain-of-function mutations, particularly those with limited or nonexistent treatment options. [ABSTRACT FROM AUTHOR]