New Therapeutic Uses for Existing Drugs.

Eighty percent of drugs that enter human clinical testing are never approved for use. This means that for every five drugs that make it into the clinic, there are four that failed to show effectiveness for treating the disease or condition the drug was designed to treat.This high failure rate means there are many existing, partially developed therapeutic candidates with known pharmacology, formulation, and potential toxicity.

Biologically active fibronectin fragments stimulate release of MCP-1 and catabolic cytokines from murine retinal pigment epithelium.

Purpose: High-temperature requirement serine protease (HTRA1) was identified as a candidate age-related macular degeneration gene in multiple genetic studies in humans. To date, no functional studies have shown a mechanism for HTRA1 to instigate ocular tissue abnormalities. In the present study, the authors focused on a substrate of HTRA1, fibronectin, because fibronectin fragments (Fnfs) stimulate biochemical events in other age-related degenerative diseases that are analogous to changes associated with age-related macular degeneration (AMD).

Delivery of Interferon-gamma by an adenovirus vector blocks herpes simplex virus Type 1 reactivation in vitro and in vivo independent of RNase L and double-stranded RNA-dependent protein kinase pathways.

HSV-1 is a significant human pathogen that can result in the loss of sight as a result of episodic reactivation of latent virus from sensory ganglion neurons. In this study the potential efficacy of anti-viral cytokine expression in preventing latent virus reactivation was investigated. Both type I (IFN-beta) and type II (IFN-gamma) IFN transgene expression following transduction of trigeminal ganglion explant cultures significantly reduced the incident of HSV-1 reactivation that in the case of IFN-beta was dependent on the presence of double stranded RNA-dependent protein kinase and RNase L.

LX211 (voclosporin) suppresses experimental uveitis and inhibits human T cells.

Purpose: To test the therapeutic effectiveness of voclosporin against experimental autoimmune uveoretinitis (EAU) in rats and to evaluate its effect on human T cells.

Methods: EAU was induced by immunization with a uveitogenic protein. Voclosporin administration, by subcutaneous injection, began on day (d) 0 or d7 after immunization.

Oligoadenylate synthetase/protein kinase R pathways and alphabeta TCR+ T cells are required for adenovirus vector: IFN-gamma inhibition of herpes simplex virus-1 in cornea.

An adenoviral (Ad) vector containing the murine IFN-gamma transgene (Ad:IFN-gamma) was evaluated for its capacity to inhibit HSV-1. To measure effectiveness, viral titers were analyzed in cornea and trigeminal ganglia (TG) during acute ocular HSV-1 infection. Ad:IFN-gamma potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN-gamma receptor.

Direct application of plasmid DNA containing type I interferon transgenes to vaginal mucosa inhibits HSV-2 mediated mortality.

The application of naked DNA containing type I interferon (IFN) transgenes is a promising potential therapeutic approach for controlling chronic viral infections. Herein, we detail the application of this approach that has been extensively used to restrain ocular HSV-1 infection, for antagonizing vaginal HSV-2 infection. We show that application of IFN-alpha1, -alpha5, and -beta transgenes to vaginal mouse lumen 24 hours prior to HSV-2 infection reduces HSV-2 mediated mortality by 2.

Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10.

Herpes simplex virus type 1 ocular infection elicits a potent inflammatory response including the production of the chemokines, CXCL9 and CXCL10, in mice. Since HSV-1 nucleic acid is recognized by pattern receptors including Toll-like receptor (TLR) 9, we tested the hypothesis that TLR9 is necessary for the early augmentation of CXCL10 following HSV-1 infection. Similar to wild type controls, TLR9 deficient mice constitutively expressed CXCL10 in the cornea.

OAS and PKR are not required for the antiviral effect of Ad:IFN-gamma against acute HSV-1 in primary trigeminal ganglia cultures.

Three interferon-gamma (IFN-gamma)-induced antiviral pathways have been reported. Involved antiviral proteins include: Mx, RNase L/2',5'-OAS, and protein kinase R (PKR). Involvement of OAS and PKR in IFN-gamma-induced anti-herpes simplex virus-1 (HSV-1) pathways has not been reported previously, but IFN-gamma induces OAS and PKR when other viruses invade the nervous system.

Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection.

We previously demonstrated that IFN-beta transgene treatment protects mouse trigeminal ganglia (TG) cells from acute HSV-1 infection in vitro. However, IFN-alpha6 transgene treatment does not provide protection against acute HSV-1 infection in vitro, even though equivalent levels of IFN are expressed with both transgene treatments. In the present study we show that IFN-beta transgene treatment before acute ocular HSV-1 infection protects mice from HSV-1-mediated mortality, whereas IFN-alpha6 transgene treatment does not reduce mortality.

Altered collagen fibril formation in the sclera of lumican-deficient mice.

Purpose: To better understand the role of lumican (corneal keratan sulfate proteoglycan) in the scleral extracellular matrix, collagen fibril size, shape, and organization were evaluated in the sclera of wild-type mice and in mice homozygous or heterozygous for a null mutation in the lumican gene. METHODS. Anterior and posterior sclera from 6-month-old wild-type (lum+/lum+) and lumican-deficient mice (lum+/lum- and lum-/lum-) were analyzed by transmission electron microscopy.