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COATs: Collagen-mimetic peptide and therapeutic gene-modified collagens for cell-mediated healing of diabetic foot ulcers

Award Number: R01DK130662
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/30/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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COATs: Collagen-mimetic peptide and therapeutic gene-modified collagens for cell-mediated healing of diabetic foot ulcers - PROJECT SUMMARY – Diabetic foot ulcers (DFU) are an enormously costly worldwide health concern. They cause nearly 80,000 lower leg amputations annually in the U.S. alone and are associated with significantly increased likelihood of death. Strategies to improve their healing have been a subject of intense study for decades, yet myriad cellular and pathophysiological abnormalities continue to severely limit efficacy of standard therapies. Promising therapeutic alternatives include the application of cellular scaffolds, topical growth factors (especially platelet-derived growth factor), or combination wound dressings. However, the incidence of complete closure remains strikingly low and growth factor delivery strategies largely fail owing to their instability in the inflammatory, MMP-rich environment of the chronic wound. New strategies that can normalize this proteolytic and inflammatory environment, by stimulating local production of therapeutic proteins by fibroblasts and macrophages, would thus offer a provocative approach to improve clinical outcomes. We have recently demonstrated that protease activity in the wound bed can be harnessed to stimulate localized growth factor gene delivery and provide tailorable expression of growth factors over multiweek timeframes. We introduce collagen mimetic peptide (CMP) and therapeutic gene-modified collagens (COATs) as a platform for (i) robust retention of growth factor-encoding polyplexes in collagen- containing wound dressings and (ii) localized, cell-initiated gene delivery during collagen remodeling. Because COATs integrate DNA polyplexes directly into collagen fibrils, our approaches have been shown to significantly improve in vivo wound repair at concentrations of growth factors orders of magnitude lower than those in currently employed topical therapies. These outcomes, coupled with recent advances in the translation of other gene therapies, suggests the high potential for clinical impact of the COATs platform. In the proposed R01 program, we will apply COATs in experimental DFUs and cell-based assays to understand three important aspects of orchestrating wound repair, in the following three Aims. In Aim 1, we will probe variations in CMP modifications that optimize the extended delivery of genes (initially for platelet-derived growth factor (PDGF)) in a murine diabetic wound environment. In Aim 2, we will complement these studies with cell-based investigations that elucidate the role of MMPs (soluble and membrane-bound) in regulating PDGF gene delivery by COATs and PDGF protein lifetime. In Aim 3, we will test how COATs-mediated, sequential delivery of genes for immunomodulatory cytokines (IL4 and IL10) modulates MMP activity in DFUs. These approaches will provide both mechanistic insights for resolving the chronicity of DFUs, and also a new platform that could be integrated into existing wound-care strategies to dramatically improve clinical outcomes.


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 = $563,758 )
2025	2025	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/2/2025	NON-COMPETING CONTINUATION	$563,758
														Subtotal = $563,758

Issue Date FY: 2024 ( Subtotal = $541,208 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/29/2024	NON-COMPETING CONTINUATION	$541,208
														Subtotal = $541,208

Issue Date FY: 2023 ( Subtotal = $540,842 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/11/2023	NON-COMPETING CONTINUATION	$540,842
														Subtotal = $540,842

Issue Date FY: 2022 ( Subtotal = $456,592 )
2022	2022	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/26/2022	NON-COMPETING CONTINUATION	$456,592
														Subtotal = $456,592

Issue Date FY: 2021 ( Subtotal = $472,220 )
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/30/2021	NEW	$472,220
														Subtotal = $472,220

Grand Total All Awards = $2,574,620

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COATs: Collagen-mimetic peptide and therapeutic gene-modified collagens for cell-mediated healing of diabetic foot ulcers

Award Number: R01DK130662

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/30/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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