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Development of first-in-class TREM-1 inhibitors for neovascular retinal diseases

Award Number: R43EY028779
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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Development of first-in-class TREM-1 inhibitors for neovascular retinal diseases - Project Summary/Abstract Retinal neovascularization (RNV) is a determinant cause of vision loss in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). In the US, about 16,000 of premature infants are affected by ROP annually and about 4.1 million adults over 40 years have DR. RVO is the second most common sight-threatening retinal vascular disorder after DR. Complications of conventional therapeutic options suggest an unmet need for new therapies. The long-term objective of this project is to develop a systemic, new mechanism-based, efficient and low-toxicity therapy for retinal neovascular diseases. Triggering receptor expressed on myeloid cells (TREM-1) is upregulated under inflammatory conditions and is involved in the angiogenic signaling pathway. In animal models of cancer, we found that blockade of TREM-1 suppresses macrophage infiltration into the tumor and improves survival. The main hypothesis of this project is that blockade of TREM-1 will inhibit macrophage/microglia infiltration into the retina and suppress RNV. In Phase I of the proposed project, we will test this hypothesis. Current TREM-1 inhibitors all attempt to block binding of the unknown ligand to TREM-1 and have a high risk of failure in clinical development. The blood-retinal barrier (BRB) represents another challenge to the systemic treatment of retinopathy. SignaBlok developed a ligand-independent TREM-1 inhibitory peptide GF9. GF9 is well-tolerated and can be formulated into SignaBlok's retina-permeable macrophage- targeted lipopeptide complexes (LPC) that contain modified peptides of human apolipoprotein A-I with epitopes for binding to scavenger receptors. Combination and exposure of these epitopes can be optimized to provide efficient and fast delivery of GF9 to the retina macrophages/microglia. This is anticipated to provide a prompt and effective therapeutic response during rapid RNV progression. Phase I specific aims are to: 1) optimize GF9-LPC composition for fast and efficient delivery of GF9 to macrophages in vitro, 2) determine pharmacokinetics, bioavailability, and biodistribution of the most promising GF9-LPC formulations and select the optimal formulation, and 3) test two doses of the optimal GF9-LPC formulation selected in Aim 2 in the oxygen-induced retinopathy mouse model. Treatment effects on vaso-obliteration and pathological angiogenesis will be assessed. Histological/immunohistochemical analysis of intraretinal macrophage/microglia infiltration and distribution of TREM-1 and markers for activated macrophage/microglial cells (Iba-1, F4/80) in relation to the RNV will be also performed. It is anticipated that the Phase I study will identify novel, first-in-class low-toxic anti-angiogenic TREM-1 inhibitors and provide a powerful platform for development of effective and safe systemic therapies for neovascular retinal diseases. If successful, Phase I will be followed in Phase II by toxicology, CMC,ADME and pharmacology studies, filing an IND application with the FDA and subsequent evaluation in humans.


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: 2021 ( Subtotal = $0 )
2021	2018	SIGNABLOK, INC.	61 FRANK ST APT 36	WORCESTER	MA	01604	WORCESTER	USA	Vision Research	000	1	9/15/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SIGNABLOK, INC.	61 FRANK ST APT 36	WORCESTER	MA	01604	WORCESTER	USA	Vision Research	000	1	7/13/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $226,223 )
2018	2018	SIGNABLOK, INC.	61 FRANK ST APT 36	WORCESTER	MA	01604	WORCESTER	USA	Vision Research	001	1	7/9/2018	NEW	$224
2018	2018	SIGNABLOK, INC.	61 FRANK ST APT 36	WORCESTER	MA	01604	WORCESTER	USA	Vision Research	000	1	5/17/2018	NEW	$225,999
														Subtotal = $226,223

Grand Total All Awards = $226,223

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Development of first-in-class TREM-1 inhibitors for neovascular retinal diseases

Award Number: R43EY028779

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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