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Compositions and methods for treating or preventing ocular infections with felocilovir

A composition and virus infection technology, applied in the field of felociclovir, treatment or prevention of human adenovirus eye infection, can solve the problems of lack of treatment of AdV conjunctivitis, unmet medical needs and the like

Pending Publication Date: 2022-04-01
MICROBION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Topical ganciclovir experimentally reduces AdV burden, but lacks efficacy in treating AdV conjunctivitis in clinical trials (Yabiku et al., "Ganciclovir 0.15% ophthalmic gel in the treatment of adenoviruskeratoconjunctivitis," Arq. Bras. Oftalmol I., 74 :417e21(2011))
[0009] In the absence of approved antiviral drugs for the treatment of ocular AdV infection, there is a significant global economic burden following ocular AdV infection (Stenson et al., "Laboratory studies in acute conjunctivitis," Arch. Ophthalmol., 100 (8):1275–1277 (1982)) and in the presence of sight-threatening complications, there is an urgent and unmet medical need for safe and effective anti-AdV agents against ocular infections

Method used

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  • Compositions and methods for treating or preventing ocular infections with felocilovir
  • Compositions and methods for treating or preventing ocular infections with felocilovir
  • Compositions and methods for treating or preventing ocular infections with felocilovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1. Cytopathic Effect (CPE) Reduction Assay to Measure Inhibition of Adenovirus 5 (AdV5) by Felocilovir.

[0151] Preparation and culture of human foreskin fibroblasts (HFF)

[0152] Human foreskin tissue was approved by the Institutional Review Board from the University of Alabama, Birmingham Tissue Procurement Facility. Tissues were stored at 4°C in aliquots supplemented with 10% fetal bovine serum (FBS; HyClone, Inc., Logan, UT) and standard concentrations of L-glutamine, amphotericin B (Fungizone), and vancomycin. In cell culture medium consisting of minimal essential medium (MEM) with Earle's salts. The tissue was then placed in phosphate buffered saline solution, minced, and rinsed to remove red blood cells. The tissue fragments were then resuspended in trypsin-EDTA solution and incubated at 37°C to disperse the cells, which were then collected by centrifugation. The cell pellet was then resuspended in 4 ml of medium and placed at 25 cm 2 tissue cultu...

Embodiment 2

[0168] Example 2. Neutral Red Survival Assay to Measure Inhibition of Adenovirus 6 (AdV6) by Felocilovir.

[0169] Neutrophil cytotoxicity assays are used to detect cell viability or drug cytotoxicity. The principle of this assay is based on the detection of viable cells via the uptake of the dye Neutral Red. Neutral Red is a dihydroazine dye that stains lysosomes in living cells. Living cells can take up neutral red via active transport and incorporate the dye into their lysosomes, but non-living cells cannot take up this chromophore. Thus, after washing, living cells can release the incorporated dye under acidified extraction conditions. The amount of released dye can be used to determine the total number of viable cells or drug cytotoxicity. Thus, cytotoxicity was expressed as a concentration-dependent reduction in neutral red uptake following exposure to the compounds under study.

[0170] Neutral red survival assays were performed in a 96-well format. Briefly, A549 a...

Embodiment 3

[0172] Example 3. Immunofluorescence Assay for AdV5 or AdV6 Infection of Felocilovir-treated Human A549 Cells

[0173] Human A549 cells on coverslips in 6-well plates were infected or mock-infected with AdV5 or AdV6 at an MOI of 5 PFU / cell. After 1 hour, Felocilovir was added to a final concentration of 40, 10, 4 or 0 μM. Twenty-seven hours after infection, A549 cells were fixed in paraformaldehyde (3.7% in PBS) and permeabilized with methanol. Cells were stained for adenovirus DNA binding protein (DBP; green in the figure) and adenovirus hexon (red in the figure). During early AdV infection (before AdV DNA replication), DBP staining will be antinuclear and uniform. As infection progresses, DBP associates with replication centers. The replication centers are initially small "dots" (each resulting from one entry into the AdV genome). As DNA replication occurs, the replication center will expand and "multiply". As the infection progresses, the nucleus becomes enlarged and d...

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Abstract

The present invention relates to therapeutic and prophylactic agents for the treatment and / or prophylaxis of ocular viral infections in humans and other mammals. Disclosed are methods of treating or preventing ocular viral infections, in particular caused by adenoviral infections, in a mammal by administering an effective amount of FCV.

Description

[0001] CROSS-REFERENCE TO PRIORITY APPLICATIONS [0002] This application claims priority to US Provisional Application No. 62 / 866,006, filed June 25, 2019, the contents of which are incorporated herein in their entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under grant R44 AI054135 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. technical field [0005] The present invention is in the field of therapeutic agents for the treatment or prevention of ocular infections and ocular diseases. In particular, the present invention relates to the use of filociclovir (FCV) in the treatment or prevention of ocular infections in mammals, and in particular in the treatment or prevention of adenovirus ocular infections in humans. Felocilovir may be advantageously used alone or in combination with anti-inflammatory, and / or antibacterial, and / or immunom...

Claims

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Application Information

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IPC IPC(8): A61K31/517A61K31/522
CPCA61K31/522A61K45/06Y02A50/30A61P27/02A61K9/0048A61P31/12A61K9/08A61K47/10A61K47/44
Inventor I·侯赛因T·L·鲍林R·高蒂尔
Owner MICROBION
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