First-in-class TREM-1 inhibitors for neovascular retinal diseases

用于治疗新生血管性视网膜疾病的一流 TREM-1 抑制剂

• 批准号: 10597284
• 负责人: Alexander B Sigalov
• 金额: $ 27.81万
• 依托单位: SIGNABLOK, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597284
• 关键词: Achievement; Adult; Affect; Angiogenesis Inhibitors; Animal Model; Antiinflammatory Effect; Apolipoprotein A-I; Area; Arthritis; Binding; Biodistribution; Biological Assay; Blindness; Blood Vessels; CSF1 gene; Cell Therapy; Child; Clinical; Complex; Data; Development; Diabetic Retinopathy; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Eye diseases; Failure; Filtration; Formulation; France; Friends; Goals; Half-Life; Histology; Human; Hypoxia; In Vitro; Inflammation; Interleukin-1 beta; Interleukin-6; Intraperitoneal Injections; Lasers; Lead; Ligands; Macrophage; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Modeling; Mus; Myeloid Cells; Oxygen; Pathologic; Pathologic Neovascularization; Pathology; Peptides; Persons; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Premature Infant; Preparation; Procedures; Rattus; Regimen; Research; Retina; Retinal Diseases; Retinal Neovascularization; Retinal Vein Occlusion; Retinopathy of Prematurity; Risk; Safety; Signal Pathway; Systemic Therapy; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxicology; Vascular Endothelial Growth Factors; Vision Disorders; conventional therapy; cost; cytokine; efficacy testing; follow-up; improved; in vivo; in vivo evaluation; inhibitor; innovation; intravenous injection; mouse model; neovascular; novel; novel therapeutics; overexpression; peptide I; prevent; protein aminoacid sequence; prototype; receptor; response; septic; side effect

Project Summary/Abstract 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 (TNFα, IL-1β, 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.

项目总结/文摘