Cardiac involvement in systemic sclerosis: A critical review of knowledge gaps and opportunities.

Cardiovascular complications are observed in up to one-third of patients with systemic sclerosis (SSc). Early identification and management of SSc-associated primary cardiac disease is often challenging, given the complex disease pathophysiology, significant variability in clinical presentation, and scarce disease-modifying therapeutics. Here, we review the molecular mechanisms involved in SSc-associated cardiac disease pathogenesis, novel diagnostic tools and emerging therapies.

Intravenous and oral administration of the synthetic RNA drug, TY1, reverses heart failure with preserved ejection fraction in mice.

TY1, a synthetic non-coding RNA (ncRNA) bioinspired by small Y RNAs abundant in extracellular vesicles (EVs), decreases cGAS/STING activation in myocardial infarction and thereby attenuates inflammation. Motivated by the concept that heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory disease, we tested TY1 in a murine model of HFpEF. Intravenous TY1, packaged in a transfection reagent, reversed the cardiac and systemic manifestations of HFpEF in two-hit obese-hypertensive mice, without inducing weight loss.

Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs.

All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated.

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury.

Unlabelled: Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates TREX1, an exonuclease that rapidly degrades cytosolic DNA.