SBIR-STTR Award

Retinal neovascularization (RNV) is a major cause of vision loss in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion. In the US, about 16,000 of premature infants are affected by ROP annually and about 4.1 million adults years have DR. Complications of conventional treatments suggest an unmet need for new therapies. The long-term objective of this project is to develop a systemic, new mechanism-based, efficient and well-tolerable therapy for ROP and other RNV diseases. Triggering receptor expressed on myeloid cells (TREM-1) is upregulated upon inflammation and is involved in angiogenic signaling pathways, suggesting TREM-1 as a promising target for treatment of RNV. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize clinical failure risks, we developed well-tolerable TREM-1 inhibitory peptides GF9 and GA31 that employ a novel, ligand-independent mechanism of action. They can be used in a free form or formulated in macrophage-specific lipopeptide complexes (LPC) to improve half-life and reduce off-target risks. Previously, we showed that ligand-independent TREM-1 blockade using either a free (GF9) or LPC- formulated peptide (GA31-LPC): 1) prevents and treats RNV in mice with oxygen-induced retinopathy (OIR); 2) improves vessel sprouting during hypoxia, 3) inhibits retinal TREM-1 and CSF-1 expression, and 4) reduces cytokine release (TNFa, IL-1ß, IL-6 and CSF-1) in vitro, while control peptides have no effect. The goal of the proposed project is to further develop this first-in-class TREM-1 therapy for neovascular retinal diseases. Considering pros and cons of GF9 and GA31-LPC, we suggest to start with both leads. Due to differences in the manifestation of vascular phenotypes, we suggest to use both OIR mice and rats. Phase I aims are to: 1) generate GMP-compliant formulations of free GF9 and GA31-LPC and test them in vitro, and 2) test the developed formulations of GF9 and GA31-LPC in the OIR mouse model. GMP-friendly tangential flow filtration technique to prepare GA31-LPC will be explored. Phase II aims are to: 1) develop an LC-MS-assay to measure GF9 and GA31 in ocular tissues, 2) test pharmacokinetics and ocular tissue distribution of GF9 and GA31-LPC in vivo, 3) test the preventative and therapeutic effects of GF9 and GA31-LPC in two OIR models and select the lead, and 4) test the lead in non-clinical toxicology studies. Comprehensive histology/IHC will be performed. Cytokines will be tested. Follow-up Phase IIb will include other administration and combination (eg, laser + GF9) regimens, GLP- TOX, ADME, CMC and other IND-enabling studies. The final product will represent safe and stable systemic therapy. Its anticipated safety is supported by safety of GF9 therapy in long-term treated healthy, cancer and arthritic mice. Prototypes of SignaBlok's LPC are well-tolerated in humans. TREM-1 blockade by SignaBlok competitor's peptide LR12 (Inotrem) is safe and well-tolerated in healthy and septic subjects.

Public Health Relevance Statement:
Project Narrative Neovascular retinal diseases affected nearly 10 million people in the U.S. in 2010 and are the leading causes of vision loss and blindness in premature infants and in people over 40 years old. Intolerance or lack of response to conventional therapies as well as serious side effects indicate an unmet need for novel treatment options. The proposed research is anticipated to result in the development of novel mechanism- based systemic therapeutics that could substantially improve treatment of neovascular retinal diseases and decrease the nation's annual cost of eye and vision disorders currently exceeding $140 billion.

Project Terms:
Achievement Attainment; Achievement; 21+ years old; Adult Human; adulthood; Adult; Affect; inhibitor; Arthritis; arthritic; Biological Assay; Assay; Bioassay; Biologic Assays; Blood Vessels; vascular; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; Diabetic Retinopathy; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eye diseases; eye disorder; ocular disease; ocular disorder; ophthalmopathy; Filtration; Filtration Fractionation; France; Goals; Half-Life; Histology; Human; Modern Man; In Vitro; Premature Infant; infants born premature; infants born prematurely; premature baby; premature infant human; preterm baby; preterm infant; preterm infant human; Inflammation; Intraperitoneal Injections; IP injection; intravenous injection; Interleukin-1 beta; Beta Proprotein Interleukin 1; IL-1 beta; IL-1 ß; IL-1-b; IL-1ß; IL1-Beta; IL1-ß; IL1B Protein; IL1F2; IL1ß; Interleukin 1beta; Interleukin-1ß; Preinterleukin 1 Beta; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Lasers; Laser Electromagnetic; Laser Radiation; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Macrophage; Mφ; Mus; Mice; Mice Mammals; Murine; Persons; Pathologic Neovascularization; Pathologic Angiogenesis; Pathological Angiogenesis; Pathological Neovascularization; Oxygen; O element; O2 element; Pathology; Peptides; Drug Kinetics; Pharmacokinetics; Phenotype; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Rattus; Common Rat Strains; Rat; Rats Mammals; Research; Retina; Retinal Diseases; Retinal Disorder; retina disease; retina disorder; retinopathy; Retinal Neovascularization; Retinal Vein Occlusion; Retinopathy of Prematurity; Retrolental Fibroplasia; premature retinopathy; Risk; Safety; Signal Pathway; Testing; Drug or chemical Tissue Distribution; Tissue Distribution; Tissues; Body Tissues; Toxicology; Vision Disorders; Visual Disorder; vision disability; cytokine; Friends; Macrophage Colony-Stimulating Factor; CSF-1; Colony-Stimulating Factor 1; M-CSF; Measures; Drug Delivery; Drug Delivery Systems; Apo A-1; Apo A-I; Apo A1; Apo AI; ApoA-1; ApoA-I; Apolipoprotein A-1; Apolipoprotein A1; Apolipoprotein AI; Apolipoprotein A-I; peptide I; improved; Procedures; Area; Clinical; Phase; Failure; Hypoxic; Oxygen Deficiency; Hypoxia; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapeutic; cellular therapy; Cell Therapy; Therapeutic; septic; Complex; Techniques; Blindness; vision loss; visual loss; Angiogenesis Inhibitors; Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenetic Antagonists; Angiogenetic Inhibitors; Angiogenic Antagonists; Angiogenic Inhibitors; Angiostatic Agents; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Antiangiogenesis Agents; Antiangiogenic Agents; Antiangiogenic Drugs; Neovascularization Inhibitors; antiangiogenic; receptor; Receptor Protein; Animal Model; Animal Models and Related Studies; model of animal; novel; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; TNF gene; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Modeling; response; Myeloid Cells; protein aminoacid sequence; peptide aminoacid sequence; peptide sequence; Molecular Interaction; Binding; VEGF; VEGFs; Vascular Endothelial Growth Factors; preventing; prevent; CSF1 gene; CSF1; MCSF; MGC31930; Dose; Data; Systemic Therapy; SYS-TX; in vivo; Antiinflammatory Effect; anti-inflammatory effect; Pathologic; Preparation; preparations; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Therapeutic Effect; Development; developmental; neovascular; cost; Biodistribution; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; prototype; overexpress; overexpression; conventional treatment; conventional therapy; efficacy testing; Regimen; Formulation; in vivo testing; in vivo evaluation; side effect