Development of advanced glycation end product (AGE)-breaking enzymes as a novel therapy for the treatment of diabetic kidney disease

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Aaron  Cravens
Organization: REVEL PHARMACEUTICALS INC.
Fiscal Year: 2024
Award: $324,015
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY
Diabetic kidney disease (DKD) is a major complication associated with Type 1 and Type 2 diabetes.
Approximately 25% of patients with diabetes develop DKD. DKD is the leading cause of kidney failure and
accounts for 44% of all end-stage renal disease cases. It is associated with heart disease and heart failure,
stroke, and early death. Treatment options for DKD are limited and focus on slowing progression to end-stage
renal disease through glycemic control. Current FDA-approved treatments do not address pathogenic
mechanisms driving the disease.
The pathophysiology of DKD is related to prolonged exposure to high blood sugar, leading to non-specific
glycation of proteins and subsequent formation of toxic advanced glycation end-products (AGEs). Evidence
suggests that accumulation of AGEs in the kidneys plays a role in the vascular complications associated with
diabetes, including DKD. Revel Pharmaceuticals is developing a novel class of therapeutics designed to cleave
one of the most abundant AGEs accumulating in DKD, carboxymethyl-lysine (CML), thus removing a
significant driver of DKD. Using rational design approaches, we have engineered enzymes that cleave free
CML and CML modified peptides.
Our goal in this Phase I grant is to optimize lead drug candidates and demonstrate enzyme activity on
physiologically relevant DKD substrates. Our specific aims are to (1) engineer CML oxidase to efficiently cleave
CML modifications from physiological substrates (2) characterize CML oxidase activity on model proteins &
human tissues. Successful completion of this Phase I SBIR project will yield the first therapeutic enzyme
designed to remove and repair AGE damage in vivo. In Phase II, we will carry out in vivo efficacy and
IND-enabling studies with our collaborators at the National Mouse Metabolic Phenotyping Center to support an
IND submission.

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diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Variant><Variation><Vascular Diseases><Vascular Disorder><Vascular Permeabilities><Work><adult onset diabetes><advanced glycation endproduct><advanced glycosylation end product receptor><advanced glycosylation endproduct><aminoacid><aminosugar><amphoterin receptor><biological signal transduction><blood damage><blood vessel disorder><brain attack><cadaveric><cadavers><carboxymethyllysine><cardiac failure><cerebral vascular accident><cerebrovascular accident><design><designing><developmental><diabetes><diabetic><directed evolution><driving><drug candidate><enzyme activity><global health><glycation><glycemic control><heart disorder><human tissue><hyperglycemic><improved><in vivo><innovate><innovation><innovative><insoluble aggregate><insulin dependent diabetes><insulin dependent type 1><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><kidney function><lead optimization><maturity onset diabetes><metabolic phenotype><metabotype><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-enzymatic glycosylation><nonenzymatic glycosylation><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><pharmaceutical><programs><protein aggregate><protein aggregation><rational design><receptor><receptor for AGE><receptor for advanced glycation end product><receptor for advanced glycation endproducts><receptor of AGE><renal><repair><repaired><resection><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic enzyme><type 1 and type 2 diabetes><type 2 DM><type I and type II diabetes><type I diabetes><type II DM><type one diabetes><type two diabetes><vascular><vascular dysfunction><vasculopathy>