PP2A Attenuates Thoracic Aneurysm and Dissection in Mouse Models of Marfan Syndrome.

Summary

In Marfan mouse models, oral activation of PP2A with DT-061 reduced aortic root and ascending aorta expansion, limited medial hypertrophy and elastin breakdown, and decreased metalloproteinase activity. Mechanistically, PP2A activation suppressed mTOR signaling and smooth muscle dedifferentiation, suggesting a disease-modifying therapeutic avenue.

Key Findings

• PP2A activity was reduced and mTOR signaling increased in human and mouse Marfan aortas.
• DT-061 increased PP2A activation and reduced aortic root/ascending aorta expansion, medial hypertrophy, elastin breakdown, and MMP activity.
• Mechanistic analyses indicate suppression of mTOR signaling and smooth muscle cell dedifferentiation as drivers of therapeutic effect.

Clinical Implications

While preclinical, the data support development of PP2A activators as potential disease-modifying therapies for heritable aortopathies (e.g., Marfan). Clinical translation will require safety profiling, dose-finding, and biomarker-driven trials.

Limitations

• Preclinical animal models without human efficacy or safety data.
• Potential off-target effects of systemic PP2A activation require careful evaluation.

Future Directions

Advance to IND-enabling studies: pharmacokinetics, toxicology, dose-ranging, and biomarker development; explore synergy or add-on to current Marfan therapies (e.g., ARBs, beta-blockers).