1. Do you remember your first “encounter” with the ACE2 molecule ?
I remember well, it was in the hallway of the Ontario Cancer Institute. My postdoc Mike Crackower had just cloned the second ACE, hence ACE2. That was around 1998/1999.
2. Which physiological role does ACE2 have within the RAAS ?
Mike Crackower then went on to generate the first ACE2 knock-out mice in the world and the data showed that the critical in vivo function of ACE2 is to counteract ACE and reduce the levels of Angiotensin II (AngII).
3. Which therapeutic potential does a recombinant soluble ACE2 have ?
AngII drives many disease pathways from heart failure to kidney and blood vessel pathologies, e.g. in diabetes, or liver and lung fibrosis, as well as in driving more severe lung injury, as we showed in the now classic papers in Nature and Nature Medicine in 2005. Knock-out ACE2 always worsened AngII driven pathologies and adding recombinant soluble ACE2 always improved it – in hundreds of experiments by multiple labs. Meanwhile, a recombinant human ACE2 version (APN01, alunacedase alfa) has been developed as a potent drug candidate. APEIRON Biologics has generated encouraging efficacy and safety results with its APN01 administered intravenously in a clinical Phase 2 trial in severely ill COVID-19 patients (NCT04335136). Importantly, APN01 should be inherently resilient to viral escape of novel virus variants of concern (alpha – delta) and further virus variants projected to become “troublesome” while some vaccines and antibodies have already started to fail. The binding affinity of APN01 has been characterized to be in the order of monoclonal antibodies with an even increased APN01 binding affinity and neutralizing potency towards variants of concern. Hence, recombinant soluble ACE2 has got the potential of a pan-SARS-CoV-2 therapeutic. APEIRON’s team is now working on a drug/device combination allowing for APN01 to be delivered directly into the airways and lungs to target SARS-CoV-2 as early as possible and prevent disease progression and viral spreading.