AGT001 for Scleroderma Kidney

SUMMARY Systemic sclerosis is an autoimmune disease that affects predominately females, and it is characterized by severe fibrosis of the skin and internal organs. Scleroderma kidney (SK) is a rare but severe complication characterized by accelerated hypertension and progressive kidney injury. Pathophysiology involves intimal thickening and proliferation of intralobular and arcuate kidney arteries leading to renal hypoperfusion, ischemia and therefore a marked increase in renin production. Consistent with this pathophysiology, Angiotensin converting enzyme (ACE) inhibitors sometimes result in dramatic improvements and, since they were introduced in the 80s, remain the primary form of therapy. However, a substantial proportion of treated patients, 20-50%, still progress to end stage kidney disease and 5-year survival is only 50-70%. Angiotensin II can drive organ fibrosis. In addition, recent work has shown concentric hypertrophy of renal arterioles in rodents and patients treated long term with RAS blockers as a result of increased numbers of renin producing cells in renal arterioles. For all these reasons there is an urgent need to identify new treatments for SK other than the widely used RAS blockers. The renin angiotensin system (RAS), however, is still an attractive and safe pathway to target new therapies for SK. We will use a renin transgenic mouse (RenTg) that replicates many of the features of the SK including intima thickening and proliferation of the renal intralobular arteries with the classic “onion skinning” appearance to determine if increasing the degradation of Ang II using our bioengineered soluble angiotensin- converting-enzyme 2 (AGT001) can provide a primary form of therapy for the SK. ACE2 is a tissue peptidase abundant in the kidneys that catabolizes Ang II. To be able to deliver ACE2 to the kidney, we bioengineered AGT001, a shorter form of ACE2, that can pass the glomerular filtration barrier. By fusing it with the Albumin binding domain (ABD) we were able to extend the duration of action from hours to days. We anticipate that the administration of AGT001 will ensure the dissipation of not only circulating Ang II but also Ang II within the kidney, thereby decreasing fibrosis within the kidney. This proposal will determine the dosing of AGT001 for efficacy when given RenTg mice to improve kidney pathology, proteinuria and hypertension in this mouse SK model. Moreover, safety and PK studies will be performed. The proposed work will lay the foundation for a novel treatment of SK based on amplification of systemic and renal ACE2 activity to lower Ang II as a strategy to mitigate long-term deleterious effects of this devastating disease. Successful completion of the proposed studies will support a Phase II application and eventually advancement of this therapy to IND-enabling studies. Our ultimate goal is to submit this novel SK therapy to the FDA for first-in-human clinical safety trials with a designation for an orphan disease.