of EPO during the proliferative phase also resulted in decreased neovascularization, suggesting that EPO may play multiple roles in this model (Chen et al. 2009).

Omega-3 PUFA, described earlier, also may play a protective role. Altering the ratio of omega-3 to omega-6 PUFA content in the retina (increasing the relative amount of omega-3) resulted in a 50% protective effect against pathological neovascularization in an OIR model (Connor et al. 2007). A similar level of protection was produced by treating with exogenous resolvins or neuroprotectins.

21.3.3.2  Therapeutics Either in Current Use and in Clinical Trials

The VEGF blocking drugs, discussed, extensively above are also being used to treat ROP. Numerous clinical trials are in progress such as NCT00622726, NCT00346814, and NCT01205035. Additionally, a trial is currently recruiting, looking at the effects of IGF-1 in the prevention of complications associated with preterm birth including ROP (NCT01096784).

21.3.4  Degenerative Conditions

In this section, we consider pathologies which lead primarily to the degenerative loss of retinal cells. The reasons for this loss may be varied. Mutations, such as those identified underlying RP, can disrupt the delicate balance maintained by the photoreceptor cell through pathological aggregation events, disruptions in metabolism, or disruptions in signaling. Alternatively, subtle changes in the shape of the eye, such as those caused by glaucoma, can put pressure on the optic nerve, cutting off the supply of trophic factors necessary for ganglion cell survival.

21.3.4.1  Pathophysiology

Retinitis Pigmentosa

RP is an inherited disease of retinal degeneration. As of this writing, 21 autosomal dominant, 32 autosomal recessive, and 4 X-linked genes have been identified (Retnet database, http://www.sph.uth.tmc.edu/retnet/sum-dis.htm#A-genes information retrieved Oct 2010). The most prevalent causes of RP are mutations in rhodopsin (25% of autosomal dominant cases), mutations in usherin (USH2A) (20% of autosomal recessive cases), and the retinitis pigmentosa GTPase regulator (RPGR) gene (70% of X-linked cases). In aggregate, the mutations within these three genes account for approximately 30% of all RP diagnoses.

Photoreceptor death in RP follows a two-stage process in which the rods degenerate first followed by the cones. Initially, the patient experiences night blindness followed by a constriction in the visual field. Finally, the patient loses central vision (Hartong et al. 2006). Most patients are declared legally blind due to a severely

constricted visual field by the age of 40. Mutations which cause photoreceptor degeneration often involve either the retinoid acid cycle or the photoreceptor signal transduction cascade. Signal transduction begins with a photon-induced conformational change of 11-cis-retinal to all-trans-retinal. This activates opsins which, in turn, trigger the cGMP phosphodiesterase; transducin, to degrade cGMP. High levels of cGMP are necessary to keep Ca++ channels open which provide the ion flux sometimes referred to as the dark current. Activation of transducin causes the channels to close due to loss of cGMP and the cell promptly hyperpolarizes. This hyperpolarization provides the force to trigger an action potential thus initiating the neural component of the visual signal. Mutations in the proteins involved in processing cGMP are prevalent in RP patients. It is curious to note that some RP mutations are found in genes which only express in rods and yet cones still die. The reason for this is not yet well understood but it may underscore a need of each photoreceptor for healthy neighbors to maintain survival.

Elevated intraocular pressure

Elevated intraocular pressure (IOP) may be caused by trauma or by glaucoma and can result in damage to the optic nerve. Retinal ganglion cell (RGC) injury may be divided into primary damage followed by secondary damage of originally undamaged cells. Secondary damage is thought to occur via the release of apoptotic inducers from the cells affected by the primary trauma and these signals, in turn, promote the destruction of neighboring RGC.

Numerous therapeutics have been developed to address elevated IOP. The most common classes of compounds used for this purpose are beta adrenergic antagonists, prostaglandin analogs, alpha-adrenergic agonists, and carbonic anhydrase inhibitors.

21.3.4.2  Therapeutics Either in Current Use or in Clinical Trials

In comparison with other ocular pathologies there are relatively few therapeutics in clinical trials and virtually no therapeutics on the market approved for retinal degenerative diseases. The current therapeutics in clinical trials are described in Table 21.4.

Cell-based therapies.  CNTF was discussed earlier in the context of AMD (Sect. 21.3.4.2). Neurotech is also sponsoring a phase II and III trial to test their CNTF expressing cells in the treatment of RP (NCT00447993). While the trial data is not yet available, phase I data indicated that changes in visual acuity, while variable, were largely positive (Emerich and Thanos 2008).

Bone marrow stem cells can be divided into those which are capable of differentiating into a hematopoietic lineage (Lin+) and those that cannot (Lin-). Lincells are of interest as they contain a subpopulation of endothelial precursor cells (EPC) which can differentiate into vascular endothelium and form new blood vessels both in vitro and in vivo (Asahara et al. 1997). These cells were shown to be capable of incorporating into the growing vasculature of the developing retina when injected intravitreally (Otani et al. 2002). Importantly, these authors also tested the effect of these cells on degenerating vasculature. They injected Lincells from normal mice

into the eyes of rd/rd mice (a model of RP) and found that the retinal vasculature was stabilized for at least a month. Surprisingly, in a subsequent study, they found that not only were retinal blood vessels stabilized, but also photoreceptors were protected through the injection of these cells (Otani et al. 2004).

Bone marrow derived stem cells (MSC) have also been explored as a source of protective factors. In the most recent example of these studies, syngeneic purified MSC were injected IV on postnatal day 30 RCS rats (Wang et al. 2010). The RCS rat is a well-established model of RP. The authors found that IV administration of MCS cells resulted in an increase in the amount of neurotrophic factors present in the retinas of these animals and retinal degeneration was significantly decreased. The University of Sao Palo is sponsoring a phase I trial in which bone marrow stem cells were introduced by intravitreal injection (NCT01068561). While the trial has completed, the results are not yet available as of this writing.

Nutritional supplements.  It was observed during a study of the natural course of RP that patients taking either vitamin A, vitamin E, or both showed a slowed degeneration of ERG amplitudes than patients not taking those supplements (Berson et al. 1993). Vitamin A is a source of retinal for the eye and it is interesting to note that mutations in at least five genes involved in vitamin A metabolism have been identified as causing RP (Hartong et al. 2006). The National Eye Institute has sponsored a trial (NCT00000116, just completed) to examine the use of 50,000 U of vitamin A daily. The results are not yet available.

Lutein, found in green leafy vegetables such as spinach has been associated with protecting retinal cells from oxidative damage. A recent clinical trial, sponsored by the National Center for Complementary and Alternative Medicine (NCT00029289) reported that lutein had a statistically significant effect on the maintenance of the size of the visual field. Visual acuity and contrast sensitivity were also improved although less so (Bahrami et al. 2006).

The omega-3 fatty acid, docosahexaenoic acid, is a precursor of neuroprotectin D1 (NPD1). NPD1 acts primarily on RPE to promote survival via protection from oxidative stress. As RPE cells are essential to the survival of photoreceptor cells it is thought that docosahexaenoic acid works indirectly to protect photoreceptor cells (Bazan 2006). The FDA Office of Orphan Products Development has sponsored a phase II clinical trial (NCT00100230) to examine the role of docosahexaenoic acid in patients with X-linked RP. The trial is ongoing.

Curcumin, an extract from Curcuma longa plants, has well-known antioxidant and anti-inflammatory activity (Epstein et al. 2010) and has been applied to ocular degenerative disease (Matteucci et al. 2010). A trial examining the efficacy of curcumin in the treatment of Leber’s Hereditary Optic Neuropathy is currently in progress (NCT00528151).

Synthetic neuroprotective compounds:  Santhera Pharmaceuticals has developed an analog of coenzyme Q10 called idebenone. It functions by inhibiting lipoperoxide formation. Santhera Pharmaceuticals is currently examining the safety and tolerability of idebenone in the treatment of Leber’s Hereditary Optic Neuropathy (NCT00747487). The trial is ongoing.