Lowering asymmetric dimethylarginine levels as a possible therapeutic strategy in pulmonary arterial hypertension

by Natalia Jarzebska.

Pulmonary arterial hypertension (PAH) is a severe, progressive condition affecting approximately 5 in 1 million people globally. If untreated, it leads to right heart failure and death, with a mean survival rate of less than three years due to its nonspecific symptoms. PAH stems from adverse vascular remodeling, increasing pulmonary flow resistance and straining the right ventricle. Current treatments, including oxygen therapy, anticoagulants, diuretics and lung transplantation, offer no cure, highlighting the need for innovative therapeutic strategies.

This project explores lowering asymmetric dimethylarginine (ADMA) – an endogenous inhibitor of nitric oxide synthases (NOS) – as a potential therapy for PAH. Elevated ADMA levels, linked to poor outcomes in PAH, disrupt nitric oxide production and promote vascular dysfunction. The study leverages a novel extracorporeal device using recombinant dimethylarginine dimethylamino-hydrolase 1 (DDAH1) immobilized on agarose beads to degrade ADMA into citrulline and methylamines. Initial ex vivo tests with human whole blood demonstrated significant ADMA reduction, though concerns about immune cell activation prompted optimization for plasma use, achieving comparable efficacy. Collaboration with Diatheva S.R.L. enabled scaled-up production of recombinant DDAH1, maintaining its purity and activity, as confirmed by enzymatic stability tests.

Currently, the team is finalizing large-scale enzyme production and testing small-volume columns to optimize flow rates and enzyme quantities. A review manuscript, “ADMA: a never-aging story,” has been accepted for publication in Hormone and Metabolic Research. This work establishes a promising foundation for reducing ADMA levels in PAH, with future efforts aimed at in vivo validation in a pig model and potential clinical translation to improve patient outcomes.