ACE2 and Ang1-7: Clinical Trials
ACE2 regulates RAS signaling by reducing Ang II/AT1 receptor signaling and by activating the ACE2/Ang1-7/Mas counterregulatory pathway. Thus far, only a few pilot clinical studies have been conducted using rhACE2 in acute respiratory distress syndrome (ARDS), sepsis, and pulmonary arterial hypertension.
Multiple murine studies demonstrated rhACE2 modulates the RAS pathway, although it is unclear if these effects translate to humans. A clinical study (Safety and Tolerability Study of APN01 [Recombinant Human Angiotensin Converting Enzyme 2]; NCT00886353) that assessed the pharmacokinetics and pharmacodynamics of soluble rhACE2 treatment in healthy volunteers with no known comorbidities showed a decrease in plasma Ang1-8 and increased Ang1-7 and Ang1-5 with no effect on blood pressure and heart rate (54). Common side effects included diarrhea and headache. No antibodies to rhACE2 developed, which suggested there was no elicit immune response to single or repeated dosing (54). Further studies investigating the immunogenicity of rhACE are required.
Serum levels of ACE and Ang II are elevated in patients with ARDS and sepsis (55,56). Studies focused on microvascular dysfunction in sepsis showed that the degree of elevation in plasma renin and Ang II were correlated with the extent of organ failure and the degree of microvascular dysfunction, especially in patients who received exogenous vasoconstrictors (56); there was also a negative correlation between re-oxygenation rates and both concentrations of plasma renin and Ang II (56). In a pilot clinical trial (Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury; NCT01597635), patients with ARDS who were treated with rhACE2 exhibited decreased plasma Ang II and elevated plasma Ang 1-7 and surfactant protein-D, which is involved in innate immunity (57). IL-6 concentrations in treated patients were also reduced, albeit statistically insignificantly, which was due to intrasubject variability and baseline imbalance. Although rhACE2 attenuated RAS mediators, infusions of the medication did not show improvement in physiological or clinical measures of ARDs in this study (57).
An additional pilot study (NCT101884051) investigated the effects of rhACE2 in human pulmonary arterial hypertension, which is characterized by reduced ACE2 activity (58). Treatment with rhACE2 showed improved cardiac output that coincided with maximum suppression of plasma cytokines and reduction in nitrotyrosine levels, improved peripheral vascular resistance, and improved renal perfusion (58).
Ongoing clinical studies assessing the modulation of RAS axis include: 1) the assessment of the relative activity of ACE and ACE2 in patients with diabetes following treatment with candesartan (Non-Insulin Dependent Diabetes Mellitus [NIDDM] and Angiotensin Converting Enzyme 2 [ACE2]: Diabetic Patients Treated With Antihypertensive Drugs; NCT00192803); and 2) the overexpression of ACE2/Ang 1-7 in cardiac progenitor cells to assess for enhancement in reparative function and the potential to attenuate myocardial ischemia−induced cardiac damage (Cardiovascular Disease Protection Tissue; NCT02348515). It is evident that targeting the ACE2/Ang1-7/Mas axis is going to be interesting in clinical settings because of the observed cardioprotective effects in the in vivo murine and in vitro cell culture models. However, further investigation is required to demonstrate whether these favorable experimental effects could be translated into clinical benefit.