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Developing Nanomaterial Platform for Intra-Cartilage Delivery of RNA Therapeutics against Joint Diseases

Award Number: R01AR072027
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract PTOA is caused by physical trauma such as sports related joint injuries. It is a common cause of joint degeneration and disability, affecting 5.6 millions of Americans every year. Currently, there is no disease- modifying drug to prevent PTOA progression. As a Nobel-prize winning discovery, small interfering RNA (siRNA) provides great therapeutic potential to specifically inhibit disease gene expression. However, it is extremely challenging to deliver negatively-charged siRNA to penetrate avascular, dense, negatively-charged cartilage matrix. Moreover, therapeutics in the joint capsule is usually cleared rapidly, limiting their residence times to as short as 1-5 hours. To overcome these obstacles, we developed a non-covalent Janus-base nano- delivery vehicle named Nanopiece (NP) with customized dimensions and surface properties, which enable the encapsulated siRNA to penetrate into articular cartilage tissue and enter chondrocytes. Through binding with extracellular matrix (ECM), NP is retained in cartilage for a long half-life, converting a barrier to carrier. The goal of this proposal is to determine the factors regulating the dimensions and surface properties of NPs, thereby 1) identifying the optimal dimensions of NPs that penetrate into cartilage effectively; 2) formulating surface properties of NPs that bind cartilage matrix for tissue retention, and 3) evaluating the therapeutic ability of the NPs to inhibit PTOA progression in the DMM model. The underlying rationale is that the completion of this proposal will 1) advance our understanding on the self-assembly of non-covalent nano-delivery vehicles and their interactions with tissue ECM molecules; 2) realize a platform siRNA delivery technology that penetrating cartilage and other matrix-rich tissues with customized dimensions and surface properties; and 3) lay the foundation for the development of the first disease-modifying RNA therapeutic against PTOA. The proposed research is innovative because: 1) NP is a new generation drug delivery vehicle with unique advantages such as the versatility in dimensions, affinity to ECM molecules and excellent biodegradability and non-toxicity. 2) We delineate the interactions between delivery vehicles and cartilage ECM in terms of the vehicles’ dimension and surface property, and then determine the key factors for successful intra-cartilage delivery. 3) The technology breakthrough enlightens a therapeutic approach to deliver siRNA to treat PTOA. After accomplishing the specific aims, we expect to 1) advance fundamental understandings of the non- covalent nanomaterial self-assembly and its interactions with tissue matrix, 2) achieve highly effective and long-lasting siRNA delivery into cartilage, and 3) inhibit PTOA progression in the DMM model via the siRNA/NP therapy. These outcomes will have important positive impact on developing specific drug delivery vehicles for cartilage or other matrix-rich tissues, and improving treatment of joint diseases such as PTOA.


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 = -$49,579 )
2025	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	11/27/2024	NON-COMPETING CONTINUATION	-$49,579
														Subtotal = -$49,579

Issue Date FY: 2022 ( Subtotal = $739,515 )
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	9/20/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	8/9/2022	NON-COMPETING CONTINUATION	$350,658
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	9/8/2022	SUPPLEMENT FOR EXPANSION	$388,857
														Subtotal = $739,515

Issue Date FY: 2021 ( Subtotal = $504,115 )
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	7/22/2021	SUPPLEMENT FOR EXPANSION	$160,541
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/29/2021	NON-COMPETING CONTINUATION	$318,780
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/8/2021	NON-COMPETING CONTINUATION	$24,794
														Subtotal = $504,115

Issue Date FY: 2020 ( Subtotal = $354,200 )
2020	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/29/2020	NON-COMPETING CONTINUATION	$354,200
														Subtotal = $354,200

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/1/2019	NON-COMPETING CONTINUATION	-$354,200
2019	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	3	5/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$91,367
2019	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,200
2019	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	5/3/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	1	5/6/2019	NEW	-$91,367
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $354,200 )
2018	2018	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/21/2018	NON-COMPETING CONTINUATION	$354,200
														Subtotal = $354,200

Issue Date FY: 2017 ( Subtotal = $354,200 )
2017	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/1/2017	NEW	$354,200
														Subtotal = $354,200

Grand Total All Awards = $2,256,651

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Developing Nanomaterial Platform for Intra-Cartilage Delivery of RNA Therapeutics against Joint Diseases

Award Number: R01AR072027

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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