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Design of a bioactive mimetic of soluble klotho for the treatment of chronic kidney disease

Award Number: R44DK132996
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Design of a bioactive mimetic of soluble klotho for the treatment of chronic kidney disease - PROJECT SUMMARY Over 37 million individuals in the U.S. have chronic kidney disease (CKD) and are at high risk to die from cardiovascular complications. While great strides have been made to improve CKD care and dialysis access, minimal advances have been made in drug development to stall or reverse kidney damage and associated pathologies. Currently, therapeutic options to prevent cardiovascular damage in CKD do not exist, and the only cure for CKD is kidney transplantation. Elevations in serum levels of phosphate and fibroblast growth factor (FGF) 23 are a hallmark of CKD and associated with an increased risk of cardiovascular death. Expression levels of klotho, a regulator of phosphate metabolism in the kidney, are reduced in CKD. Klotho can be released from the kidney as soluble klotho (sKL) that circulates in the blood and acts as a binding partner for FGF receptors (FGFR) on various tissues. Reductions in serum sKL levels have been shown to contribute to CKD-associated pathologies. sKL seems to protect tissues by substituting for renal klotho thereby promoting FGF23/FGFR1- induced renal phosphate excretion and lowering systemic phosphate levels, as well blocking the direct pathologic actions of FGF23 and of paracrine FGFs. While elevating klotho expression has shown therapeutic potential in animal models of CKD, further advances have been stymied by sKL’s short half-life and technical difficulties to produce the recombinant sKL protein in sufficient amounts, along with a lack of tools to measure sKL activity. Alpha Young LLC has developed a novel method to produce the recombinant sKL protein as well as a novel assays to determine the bioactivity of sKL based on its ability to bind FGF23 and FGFR1. We have generated an early-stage mimetic protein, and here we will introduce additional point mutations to increase sKL’s stability and bioactivity. In Phase 1, we will modify sKL’s glycosylation sites and heparin binding domain, and we will screen for mutant variants with increased binding affinities for FGF23 and FGFR1 to improve bioactivity, and decreased heparin binding affinity to increase half-life. In Phase 2, we will optimize our identified sKL variants by utilizing a phage display-based approach to introduce mutations into sKL’s FGFR binding domain with the goal to increase FGFR1 binding affinity. Candidates with the desired changes in binding properties will be tested for their biological activity using cell culture models that can determine the effect of sKL on FGF23-regulated signaling, renal phosphate uptake, cardiac hypertrophy and on fibroblast activation induced by paracrine FGFs. The half-life of the most promising candidates will be tested by injection studies in in rats. Finally, the most active and stable sKL variant will be injected into mouse models of CKD, followed by the analysis of renal phosphate excretion and cardiovascular damage. We propose that the administration of our sKL mimetic can serve as a novel therapeutic approach in CKD to lower serum phosphate levels and to protect from the damaging actions of FGFs. A successful completion of our project would provide us with a potent drug candidate and the opportunity to pursue early-stage partners for advancing and validating its potential for future clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	ALPHA YOUNG LLC	5353 PARKSIDE DR RM 229E	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/31/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $543,558 )
2024	2024	ALPHA YOUNG LLC	652 PROVENCE DR	VESTAVIA	AL	35242	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/21/2024	NON-COMPETING CONTINUATION	$543,558
														Subtotal = $543,558

Issue Date FY: 2023 ( Subtotal = $606,474 )
2023	2023	ALPHA YOUNG LLC	652 PROVENCE DR	VESTAVIA	AL	35242	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/18/2023	EXTENSION WITH OR WITHOUT FUNDS	$606,474
2023	2022	ALPHA YOUNG LLC	652 PROVENCE DR	VESTAVIA	AL	35242	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/3/2023	NEW	$0
														Subtotal = $606,474

Issue Date FY: 2022 ( Subtotal = $256,050 )
2022	2022	ALPHA YOUNG LLC	652 PROVENCE DR	VESTAVIA	AL	35242	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/5/2022	NEW	$256,050
														Subtotal = $256,050

Grand Total All Awards = $1,406,082

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Design of a bioactive mimetic of soluble klotho for the treatment of chronic kidney disease

Award Number: R44DK132996

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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