Research focused on identified new targets

Use of neurotrophic factors as a treatment for retinal degenerative diseases is in its early phase. A few products are making their way through clinical trials; however, many of the possible targets have yet to make it to the clinic. Several neurotrophic factors have been examined in the context of RGC protection. The FGF family has been shown to play an important role both in the development of the brain, in general (Abe and Saito 2001) and in the retina, in particular (Hicks 1998). FGF receptors are expressed in the developing retina and appear to be essential for appropriate development to occur. Initial attempts to use FGF-2 as a therapeutic agent via intravitreal injection failed (Cui et al. 1999). Sapieha et al. (2003, 2006), however, reasoned that as FGF-2 is quite labile the failure may be due more to the mode of delivery than to the efficacy of the molecule. Indeed, they found that by injecting the vitreous chamber with an FGF-2 expressing adeno-associated virus (AAV) they were able to promote significant axonal growth via an Erk related signaling cascade. Unfortunately, this growth was limited to 1 mm from the lesion site. FGF2 among other factors is upregulated by the expression of leukemia inhibitory factor (LIF). LIF expression was found to be upregulated in a subset of Müller glial cells after axonal injury (Joly et al. 2008). Exogenous application of recombinant LIF via intravitreal injection was found to activate a complex genetic pathway associated with retinal protection including the upregulation of Edn2, STAT3, FGF2, and GFAP. Müller cells have the interesting ability to dedifferentiate into progenitor cells of which a few will then differentiate into neurons. FGFR activation along with the activation of the ERK pathway has recently been shown to promote this transformation of Müller cells into progenitor cells (Fischer et al. 2009).

21.3.5  Opportunistic Infections

21.3.5.1  Pathophysiology

Uveitis involving posterior ocular structures is most often caused by infection. In this context, we are not considering an otherwise healthy patient, but rather, a patient who is immunosuppressed and is now vulnerable to an opportunistic infective agent. Immunosuppression can occur for a variety of reasons. Perhaps the most common reason at present is HIV infection and the development of AIDS. Other reasons may include chemotherapy, immunosuppression for organ transplant, pregnancy, and malnutrition. A discussion of the mechanisms by which the immune system protects us from infection is beyond the scope of this chapter and ultimately is not pertinent to the mechanisms by which anti-infective agents function. Posterior uveitis involves inflammation of structures such as choroid, retina, vitreous, optic nerve head, and retinal vessels (Sudharshan et al. 2010).

We may divide the universe of pathogens which commonly infect ocular structures to viruses, parasites, and bacteria. Viruses which we will consider here include CMV, herpes simplex virus, and varicella zoster. Parasites to be considered include

toxoplasmosis (Toxoplasma gondii) and toxocariasis (helminthic round worm) (Klotz et al. 2000). Finally, we will consider bacillus tuberculosis (TB), syphilis, and bartonella (Sudharshan et al. 2010).

21.3.5.2  Therapeutics Either in Current Use or in Clinical Trials

Viral targets

CMV:  CMV retinitis is the most common AIDS-related opportunistic infection in the eye and manifests as one of two distinct clinical patterns (Vrabec 2004). The indolent form of CMV retinitis is characterized as granular lesions in the peripheral retina. In turn, severe CMV retinitis is characterized by hemorrhage in the posterior retina. Treatment of CMV retinitis can be achieved by antiretroviral agents of highly active antiretroviral therapy (HAART) and anti-CMV agents (Vrabec 2004) (Table 21.5).

Anti-CMV agents include ganciclovir, foscarnet, cidofovir, and fomivirsen (Table 21.6). Ganciclovir is a guanosine nucleoside analog derivative. It acts by competitively inhibiting DNA polymerase of CMV, and thereby prevents DNA replication. Valganciclovir is a prodrug of ganciclovir with an improved bioavailability. Foscarnet is an organic analog of inorganic pyrophosphate. It is both an inhibitor of pyrophosphate binding site of DNA polymerase of CMV and reverse transcriptase of HIV. Cidofovir acts by competitively inhibiting CMV DNA polymerase and consequently inhibits DNA replication. Fomivirsen is an antisense oligonucleotide which acts by binding to mRNA of major immediate-early transcriptional unit of CMV and results in degradation of this viral transcript. Therefore, Fomiversen slows down viral replication.

Herpes simplex and varicella zoster viruses:  Necrotizing herpetic retinopathy (NHR) is most commonly caused by herpes simplex and varicella zoster viruses. NHR is clinically presented in two forms, ARN and progressive outer retinal necrosis (PORN) (Vrabec 2004). NHR is characterized by vitritis, peripheral retinitis, and retinal arteritis. Treatment can be achieved by long-term systemic antivirals such as acyclovir or valacyclovir (Sudharshan et al. 2010).

Parasitic targets

Ocular toxoplasmosis:  Ocular toxoplasmosis is caused by Toxoplasma gondii. Most individuals infected with T. gondii will not develop ocular disease. However, two specific populations are particularly at high risk: immunocompromised patients such as HIV-acquired patients, and neonates who have been exposed transplacentally by mother’s infection (Feldman 1982). Toxoplasmosis causes necrotizing chorioretinitis most commonly in the posterior pole. The ideal treatment for this pathogen has not yet been indentified (Sudharshan et al. 2010). Current treatment strategies target the trophozites of T. gondii. However, the best strategy is to target cysts of T. gondii (Sudharshan et al. 2010). Pyrimethamine in combination with sulfadiazine has a synergistic effect and is perhaps the most effective treatment. Currently, classic treatment consists of drugs such as sulfadiazine, pyrimethamine, folic acid, and a corticosteroid. Other treatments that have had success include clindamycin, trimethoprim plus sulphamethoxazol, spiramycin, zaithromycin, and atovaquone