MOA

In brief: I discover therapeutically actionable drug mechanisms hidden in public data.

MOA, or mechanism of action, is a crucial bottleneck in drug development. To obtain investor interest and regulatory approval, a drug program needs a convincing biological mechanism validated in vitro and supported by robust external evidence. Insight into the mechanism can, in turn, help define the scope of indication, stratify populations to identify the patients who would best benefit from the drug, and determine the appropriate conditions, readouts, and subjects for clinical trials.

I supported MOA efforts for a cardiopulmonary drug program at Fauna Bio by curating, analyzing, and integrating large volumes of public data from heart, lung, and peripheral nerve tissues across species. These investigations have underlined how many “low-hanging fruit” remain and how much we have left to learn from large, publicly available datasets that have undergone only cursory analysis. In one instance, I have discovered and reported the unexpected expression of the female-specific gene XIST in the male heart nervous system, possibly involved in a previously unknown regulatory role and associated with heart disease.

Finally, the mechanistic investigations provided me with opportunities to analyze restrospectively collected clinical data. These datasets are especially rich, as they present natural experiments to evaluate the effect of interventions on patient vitals and survival. However, they present layers of complexity well beyond bioinformatic readouts: the data are noisy, idiosyncratic, and often incomplete. I closely collaborated with experts in pharmacological MOA to refine patient cohorts and improve statistical analyses.

XIST is a long non-coding RNA that mediates the process of X chromosome inactivation in females, and has not been previously observed in males outside of developmental, pathological, and ectopic contexts. We report the unprecedented endogenous expression of XIST in 226 male heart samples across 15 single-cell RNA sequencing studies. The male expression of XIST is specific to a rare cell type typically annotated as neurons or glia. We investigate a variety of explanations and cross-reference the expression of XIST against age, sex, and pathology, finding signatures of a non-canonical inhibitory program, potentially mediated by a truncated transcript. Interestingly, the highest-powered datasets exhibit XIST upregulation in heart disease and comorbidity donors relative to healthier controls. Furthermore, in humans we identify a male-specific association of the XIST genomic locus with myocardial infarction (p = 1.3 × 10⁻⁴). Taken together, our findings suggest that the pathology of cardiomyopathy may involve uncharacterized, therapeutically actionable non-coding RNA pathways that operate through the cardiac nervous system, and underscore the importance of genomic investigations of the X chromosome.

References

2026