AGT001 for Delayed Graft Function in Kidney Transplantation

Project summary Delayed graft function (DGF) is a form of acute kidney injury (AKI) that affects up to 50% of deceased-donor kidney transplant recipients. Because of the organ shortage crisis, marginal or expanded criteria for donor kidneys are increasingly considered even though these kidneys are at higher risk to develop DGF. There are no FDA approved treatments for DGF available to date. Treatment or prevention of delayed graft function, therefore, poses an unmet clinical need and new approaches to prevent and attenuate DGF are urgently needed. DGF is largely caused by acute proximal tubular injury induced by ischemia/reperfusion injury. Angiotensin converting enzyme 2 (ACE2) is a tissue monocarboxypeptidase abundant in the kidney proximal tubule that, among other substrates, cleaves the amino acid phenylalanine from Angiotensin (Ang) II to form Ang 1-7. With deficiency of ACE2, Ang II accumulates, and the excess of this peptide results in increased inflammation, fibrosis, and oxidative stress, all of which are features of acute kidney injury (AKI) and the AKI associated with DGF. We have strong preliminary data in a preclinical mouse model of DGF caused by 3 hours of cold ischemia prior to syngeneic kidney transplantation showing that ACE2 distribution in the kidney is profoundly altered. The membrane bound form of ACE2 is lost from the apical brush border of tubular cells and deposited in the tubular lumen and excreted in the urine. Decreased kidney ACE2 suggests a contributing effect to the causation/severity of DGF that could be targeted therapeutically by administering a suitable form of soluble ACE2. To deliver ACE2 to the kidney and thereby lower Ang II levels our lab designed a soluble ACE2 protein bioengineered to pass the glomerular filtration barrier by shortening the native form to only 618 amino acids This truncate was later fused with an Albumin binding domain (ABD) to extend the duration of action from hours to days. Our preliminary data show that prior administration of this protein, termed AGT001, to mice that develop DGF after syngeneic kidney transplantation results in kidney protection as shown by reduced blood urea nitrogen (BUN) and reduced kidney Ang II levels. In this proposal, we will determine the dosing of AGT001 for efficacy and safety when given perioperatively to attenuate DGF in mouse syngeneic and allogeneic kidney transplantation models. The proposed work will lay the foundation for transplantation of human donor kidneys enriched with ACE2 activity in-vivo as a strategy to mitigate DGF and expand the use of marginal kidney donors. Successful completion of the proposed studies will support a Phase II STTR application and eventually advancement of this therapy to IND-enabling studies. Our ultimate goal is to submit AGT001 to the FDA for consideration for first-in-human clinical safety trials.