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Erythrocyte-derived particles for near infrared phototherapy of port wine stains.

Award Number: R01AR068067
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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Erythrocyte-derived particles for near infrared phototherapy of port wine stains. - Port wine stain (PWS) is a congenital and progressive malformations of the dermal capillaries. Pulsed dye laser (POL) irradiation in the visible wavelength range of 585-600 nm remains as the gold standard of treatment. The underlying treatment principle is based on the absorption of POL light by hemoglobin to induce irreversible photothermal coagulation of the vasculature. However, therapeutic efficacy with POLs remains limited due to insufficient penetration of light in skin, and non-specific absorption by the epidermal melanin pigments. Clinically acceptable outcomes are achieved in only about 20% of patients with diminishing returns beyond five treatment sessions. Our long-term objective is the development of a new therapeutic approach based on intravascular administration of optical micro-particles, fabricated from erythrocytes, as targets for pulsed near infrared (NIR) laser treatment at 755 nm. These micro-particles are doped with indocyanine green (ICG), the only FOA-approved NIR chromophore. The underlying premise is based on reduced absorption of light by melanin, strong ICG absorption, and availability of dermatological lasers at 755 nm. A particularly innovative feature of these micro-particles is that their membrane is enriched with cholesterol to prevent the flipping of phosphatidylserine from the inner to the outer leaflet of the membrane, which would otherwise serve as a signal for removal of the particles from the vasculature. We refer to these micro-particles as c⁺- µNETs. By using c⁺-µNETs, we aim to prolong the circulation time of ICG, and increase its availability in the lesion vasculature so that more sites can be treated during a given session, ultimately leading to minimal therapeutic sessions to clear the stain. Another innovative aspect is the use of transgenic mice whose melanin content can be varied in a controllable manner to simulate the epidermal response of PWS with different pigmentations to 755 nm laser irradiation. We will use these mice to determine the threshold values of the laser radiant exposures for epidermal injury and blood vessels photocoagulation in conjunction with c⁺-µNETs. We will also use a rabbit model to characterize the circulation and biodistribution dynamics of c⁺-µNETs, determine the therapeutic window of time when using c⁺-µNETs, and evaluate the vascular response as it relates to laser irradiation parameters and dose of c⁺-µNETs. SA 1: Fabricate and characterize c⁺-µNETs. SA 2: Characterize the circulation and biodistribution dynamics of c⁺-µNETs. SA 3: Evaluate the therapeutic efficacy of c⁺-µNETs in conjunction with pulsed NIR laser irradiation. A key outcome of our proposed studies is that we will know the maximum length of time over which effective blood vessels photocoagulation can be achieved when using c⁺-µNETs, in addition to finding the appropriate radiant exposure levels for vascular photocoagulation in skins with various pigmentations. This knowledge is not currently available, but is essential towards development of safe and effective protocols for laser treatment of PWS patients. Proposed studies are consistent with the scientific themes of NIAMS in developing effective therapies for PWS.


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 = $452,171 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	3/14/2025	NON-COMPETING CONTINUATION	$452,171
														Subtotal = $452,171

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $515,198 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	2/27/2023	NON-COMPETING CONTINUATION	$515,198
														Subtotal = $515,198

Issue Date FY: 2022 ( Subtotal = $534,208 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	5	6/9/2022	COMPETING CONTINUATION	$16
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	4/5/2022	COMPETING CONTINUATION	$57,261
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/28/2022	COMPETING CONTINUATION	$476,947
2022	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	6/9/2022	NON-COMPETING CONTINUATION	-$16
														Subtotal = $534,208

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $331,878 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/13/2019	NON-COMPETING CONTINUATION	$331,878
														Subtotal = $331,878

Issue Date FY: 2018 ( Subtotal = $332,722 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/9/2018	NON-COMPETING CONTINUATION	$33,273
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2018	NON-COMPETING CONTINUATION	$299,449
														Subtotal = $332,722

Issue Date FY: 2017 ( Subtotal = $333,874 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$33,388
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/28/2017	NON-COMPETING CONTINUATION	$300,486
														Subtotal = $333,874

Issue Date FY: 2016 ( Subtotal = $332,892 )
2016	2016	REGENTS, UNIVERSITY OF CALIFORNIA	POST OFFICE BOX 112	RIVERSIDE	CA	92521	RIVERSIDE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/10/2016	NEW	$332,892
														Subtotal = $332,892

Grand Total All Awards = $2,832,943

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Erythrocyte-derived particles for near infrared phototherapy of port wine stains.

Award Number: R01AR068067

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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