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Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing

Award Number: R43AR062418
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2012
PERIOD OF PERFORMANCE END DATE: 04/30/2014

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Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing - DESCRIPTION: In 2010, more than 875,000 Americans with diabetes were diagnosed with a lower extremity ulcer. Failed closure of these wounds results in more than 73,500 lower extremity amputations annually. Valitor, Inc. is developing protein-polymer therapeutics to overcome the microvascular consequences of diabetic wound healing. We designed our therapy to complement the standard practice of diabetic ulcer management and to reduce the costly serial effort required for debridement and clinical observation of these slowly healing wounds. Our patented technology is a chemical tethering process that enables us control the valency of growth factors that are delivered within the vicinity of a receptor. With this technology, we have conjugated Sonic hedgehog (Shh), an important angiogenic factor, to linear chains of hyaluronic acid (HyA), and by varying the ratio of Shh: HyA, we can modulate its ability to activate the Shh pathway. Conjugating Shh to a large macromolecule may also prevent its deactivation by proteolytic enzymes and enhance its molecular stability in the target tissues. We will develop these multivalent Shh (mvShh) conjugates as a treatment to accelerate wound healing in diabetic lower extremity ulcers, as Shh has previously been shown to stimulate neovascularization. The Valitor approach to Shh therapy will enable enhanced Shh bioactivity in vivo, and delivery of our therapeutic into the wound bed could provide a significant improvement in the patient's long-term outcome at a low treatment cost. Our overall goal during Phase I is to develop mvShh conjugates that elicit enhanced Shh pathway activation and downstream angiogenic gene expression in the cell types that coordinate cutaneous wound healing. In Specific Aim 1, we will identify the mvShh formulations that yield maximal Shh pathway activation in vitro using dermal fibroblasts harvested from db/db mice, a diabetic model animal that exhibits impaired wound healing and diminished angiogenic gene expression. We will then determine the effect of Shh valency on microvascular endothelial cell proliferation and migration in vitro, as these are essential mechanisms required for angiogenesis. In Specific Aim 2, we will demonstrate proof-of-principle that the mvShh conjugates will initiate Shh signaling and downstream angiogenic gene expression in db/db mice using a full-thickness excisional wound model. Our findings will provide valuable proof-of-concept data for further pre-clinical development of our therapeutic, which we have planned for Phase II of this project. PUBLIC HEALTH RELEVANCE: Relevance In 2010, more than 875,000 Americans with diabetes were diagnosed with a chronic lower extremity ulcer, and these patients generate over $30 billion per year in related health care costs. Valitor, Inc. is developing an advanced therapeutic to accelerate healing in diabetic wounds, offsetting the high cost of treatment by encouraging neovascularization and improving blood supply in the wound bed. The overall goal of our Phase I project is to relate the treatment parameters of our therapeutic to the cellular mechanism of blood vessel formation and demonstrate proof-of-concept for our technology as a clinical therapy.


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: 2017 ( Subtotal = -$1,653 )
2017	2012	VALITOR, INC.	820 HEINZ AVE	BERKELEY	CA	94710	ALAMEDA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/14/2017	NEW	-$1,653
														Subtotal = -$1,653

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	VALITOR INC	3841 COMPOLINDO DRIVE	MORAGA	CA	94556	CONTRA COSTA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/1/2014	NEW	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $311,158 )
2012	2012	VALITOR INC	3841 COMPOLINDO DRIVE	MORAGA	CA	94556	CONTRA COSTA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/10/2012	NEW	$311,158
														Subtotal = $311,158

Grand Total All Awards = $309,505

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Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing

Award Number: R43AR062418

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2012

PERIOD OF PERFORMANCE END DATE: 04/30/2014

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