CHEST Guidelines-Ineffectiveness-of-Sotatercept-Therapy-in-a-Patien

Ineffectiveness-of-Sotatercept-Therapy-in-a-Patien

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A report discusses the ineffectiveness of Sotatercept treatment in a patient with heritable pulmonary arterial hypertension (PAH) linked to a previously unreported missense variant in the GDF2 gene. This gene encodes bone morphogenic protein-9 (BMP9), essential for proper pulmonary microvasculature function. PAH often results from an imbalance between anti-proliferative BMP receptor-2 signaling and pro-proliferative activin receptor signaling, with Sotatercept, acting as an activin ligand trap, usually providing clinical benefits by correcting this imbalance.<br /><br />The patient in question, diagnosed with idiopathic PAH and a familial history suggestive of Mendelian inheritance, exhibited a rare GDF2 gene variant labeled as a variant of unknown significance (VUS). Genetic testing revealed that the variant has the potential to disrupt important protein structures, indicating it might be pathogenic despite its current classification.<br /><br />Despite starting Sotatercept in 2022, the patient experienced no clinical improvement. This lack of response may be tied to the variant's disruption of BMP9 functions—critical for the endogenous signaling that Sotatercept aims to modify. BMP9 typically partners with type-II activin receptors, and a deficiency can contribute to PAH, suggesting that Sotatercept's mechanisms might be ineffective in cases involving certain GDF2 mutations.<br /><br />This case underlines the importance of precision medicine in PAH treatment, advocating for genetic screening to guide therapy. Such screening could prevent ineffective treatments, saving time and resources by identifying genetic causes that render some therapies, like Sotatercept, non-beneficial. This approach may lead to more tailored and effective treatments for individuals with specific genetic backgrounds contributing to PAH.

Keywords

Sotatercept

heritable pulmonary arterial hypertension

GDF2 gene

missense variant

bone morphogenic protein-9

BMP9

activin ligand trap

precision medicine

genetic screening

idiopathic PAH