INTRODUCTION

Hereditary retinal diseases are a group of diseases that are slowly progressive and may lead to severe visual disability. These are orphan diseases, which, in the USA, are defined as conditions affecting fewer than 200,000 people. A majority of these conditions have no proven means of treatment. However, more and more genetic mutations are being identified, which provides a better understanding of the pathophysiology of these diseases. Thus, the past decade has seen a tremendous growth in therapeutic research in these diseases.

The retina, retinal pigment epithelium (RPE), and choroid form an important complex and are functionally interdependent. Even though the mutant gene may be expressed in only one of these layers and cause apoptosis, the other two layers degenerate in the corresponding areas as well. Treatment for these conditions can be in the form of replacing the gene (as in Leber’s congenital amaurosis (LCA)), providing growth factors to sustain the degenerating photoreceptors (ciliary neurotrophic factors (CNTF) in retinitis pigmentosa (RP)), or dietary restriction of a toxic protein that is not being metabolized in the retina (phytanic acid in Refsum disease). Some of these degenerative diseases that have a therapeutic valence are discussed in this chapter.

SPECIFIC DISEASES

RETINITIS PIGMENTOSA

RP is a group of inherited retinal diseases that affects approximately 1 in 4000 people. The mode of inheritance can be autosomal-recessive, autosomal-dominant, or X-linked recessive. Symptoms of RP include problems with night vision and peripheral vision. The central vision is also affected. Fundus examination shows a pale-appearing optic nerve, attenuated arterioles, and bone-spicule pigmentary changes in the mid peripheral retina (Figure 28.1). Visual field testing shows a concentric restriction or ring scotoma, eventually leading to “tunnel vision.” Electroretinography (ERG) shows reduced or absent rod function with subsequent reduction of cone function. RP can be associated with cystoid macular changes and atrophic lesions in the fovea.

Nutrients and retinitis pigmentosa

RP has no treatment yet. A report in 1993 concluded that an oral supplement of high-dose vitamin A palmitate (15,000 IU/day) is helpful in slowing down the progress of disease.1 Although this was a wellplanned, randomized, controlled, and double-masked study, the interpretation was considered controversial.2,3 The results of the study concluded that patients who were on this high dose of vitamin A had less decline of cone ERG amplitudes. However, none of the other retinal function tests, including visual acuity and visual field, were significantly affected. Moreover, there was concern that this high dose of vitamin A is teratogenic and when taken over years may be hepatotoxic and possibly cause osteoporosis. The same study also reported possible

accelerated course of the disease with vitamin E supplementation. Hence, vitamin E is not recommended in patients with RP.

Docosahexaenoic acid (DHA) is a long-chain, omega-3 fatty acid that is normally found in red blood cell (RBC) membranes and outer segments of rod photoreceptors. Significant correlation between the DHA levels in RBCs and ERG amplitudes has been reported. A phase I trial with supplementation of 400 mg/day of DHA in patients with X-linked RP for a period of 4 years did not show any adverse toxic effects.4 Furthermore, there was no statistically significant difference in the rate of loss of cone ERG amplitudes between the treated and untreated groups. Also, there was no change in visual function between the two groups. Another study investigated the effect of 15 000 IU vitamin A with or without 1200 mg/day DHA in patients with RP. No significant difference was reported in the ERG amplitudes between the two groups

– hence, DHA is not yet recommended as a treatment.5

Cystoid Macular Edema (CME) associated with RP

CME is present in 15–20% of patients with RP. With the advent of optical coherence tomography (OCT), the incidence is even higher.6 Macular edema may be evident on clinical examination, fluorescein angiography, and/or OCT. Although the mechanism of CME is not clear, the assumption is that the RPE cells are unable to pump out the fluid from the outer retina. Treatment of CME consists of carbonic anhydrase inhibitors (CAIs). Systemic CAIs like acetazolamide7 and methazolamide8 can lead to resolution of macular edema with improvement in visual function in some patients. However, they can cause side-effects like fatigue, tinnitus, “tingling” sensation in the extremities, loss of appetite, and renal stones. Rarely, more serious problems like aplastic anemia and agranulocytosis have been reported. Topical dorzolamide (used three times a day) is also effective in some patients in reducing the CME with improvement in visual acuity.9 However, the CME should be monitored with OCT at regular intervals as both systemic and topical CAIs can cause a “rebound phenomenon,” whereby the CME can get worse while still on treatment.9–11

Ciliary Neurotrophic Factor and retinitis pigmentosa

Neurotrophic factors like basic fibroblast growth factor and CNTF have been shown to have a neuroprotective role on degenerating photo­ receptors in animal models, CNTF being the most common. Although this has been known for several years, the mode of drug delivery was difficult. It could not be given orally or intravenously because of relative impermeability of the blood–retina barrier. Since CNTF was found to be neurotoxic in large doses, leading to decrease in ERG amplitudes,12,13 it could not be injected intravitreally.

Based on the fact that CNTF may be useful in optimal concentrations only, a drug delivery device (NT-501, Neurotech, USA) was developed using encapsulated cell technology. This is a 6-mm long semipermeable intravitreal implant that consists of a hollow fiber membrane containing genetically modified human cells secreting CNTF at a fixed concentration (Figure 28.2A). The fiber membrane is designed so that it permits