Multitargeted Therapy for Age-related Macular Degeneration
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a sight-threatening disease which represents the leading cause of blindness and visual impairment in elderly individuals in developed countries. Recently, laser and photodynamic therapies with limited clinical benefit have been partially replaced by anti-vascular endothelial growth factor (VEGF) therapies. Clinical studies have demonstrated that anti-VEGF therapeutics can slow or reverse the progression of wet-AMD. However, these therapies, which target a single molecule only, do not benefit all patients with AMD. AMD is a complex disease involving numerous molecular pathways that are implicated in angiogenesis, inflammation and other pathological processes of AMD. Thus, thereis a great demand for developing new drugs targeting multiple molecular pathways to improve the treatment of AMD. Through screening a series of a novel small molecule compounds to inhibit retinal neovascularization (NV) inflammation and vascular permeability, we have identified a novel compound, CLT-003, as a potential multi- targeted drug. The novel compound attenuated the activation of hypoxia-inducible factor-1alpha (HIF-11) and nuclear factor kappaB (NF B), and down-regulated the expression of VEGF inaddition to the inflammatory intercellular adhesion molecule-1 (ICAM-1). These molecules are all pathogenic factors in AMD development. HIF-11 and NF B are the master transcription factors which regulate many genes associated with angiogenesis and inflammation, such as VEGF and ICAM-1. Therefore, HIF-11 and NF B likely are the main targets of CLT-003. Our studies demonstrated that CLT-003 inhibited the endothelial cell growth, migration and tube formation, arrested endothelial cell cycle and induced endothelial cell apoptosis; CLT-003, however, did not significantly affect the growth of normal cells (e.g. pericyte and lung fibroblast), suggesting endothelial cell-specific growth inhibition. CLT-003 inhibited angiogenesis in both chicken chorioallantoic membrane (CAM) and rat oxygen- induced retinopathy (OIR) models, and blocked retinal vascular leakage in both AMD and diabetic retinopathy animal models. CLT-003 had significantly higher potency to block vascular leakage as compared to Kenalog which is currently used clinically. Moreover, pharmacokinetic studies showed the CLT-003 was cleared rapidly following an intravenous injection in animals. Such pharmacokinetic profile of CLT-003 is appropriate as an ocular drug. Toxicity studies showed that high doses ofCLT-003 were well tolerated in animals. These findings suggest that CLT-003 has potent anti-angiogenic, anti-inflammatory and anti-vascular permeability activities through targeting multiple molecular pathways, while exhibiting a highly favorable safety profile. Intravitreal administration is an efficient route for ocular drug delivery and offers high local concentrations in the vitreous and retina. However, frequent and repeated intraocular injections are undesirable in a clinical setting due to patient/physician burden, the increased risk of ocular infection and other side effects; thus, it is desirable to develop an ocular drug delivery system which mediates sustained release of ocular drugs. Nanoparticle-mediated drug delivery systems are widely considered a safe and efficient method for ocular drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is a FDA-approved copolymer which is used as a carrier for drugs, owing to its biodegradability and biocompatibility. To overcome the short duration of the effects of the ocular drug after an intravitreal injection and maintain a sustained efficacious level of ocular drug in the eye, we have developed a PLGA CLT-003 nanoparticle (CLT-003NP) formulation. CLT-003NP mediated the sustained release of CLT-003 over 16 weeks, had a prolonged inhibitory effect on endothelial cell growth and significantly reduced retinal vascular leakage in diabetic retinopathy rats for at least 6 weeks. Taken together, CLT-003NP is a promising drug candidate for the long-term treatment of AMD as it targets multiple pathological factors in AMD development and can achieve prolonged efficacy. This phase I project including two specific aims will serve as a proof-of-concept study to evaluate the anti-angiogenic and anti-inflammatory efficacies of CLT-003NP in a rat choroidal neovascularization (CNV) model: 1) To evaluate the effect of CLT-003NP on angiogenesis. CNV is responsible for 75% of the severe vision loss attributable to AMD patients. Using a rat CNV model induced by laser, we will determine whether CLT-003 is capable of preventing CNV development and arresting CNV progression. 2) To determine the effect of CLT-003 on inflammation. Inflammation plays a crucial role in AMD pathogenesis. In the same animal model, we will explore whether CLT-003 has an anti-inflammatory effect. These studies will lay a solid ground for further studies in SBIR phase II toward developing CLT-003NP to become a novel and multi-targeted drug to improve the treatment of AMD.
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