Retinitis Pigmentosa A Model Neurodegenerative Disease

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As people age, they often lose not only cognitive function but also visual, auditory, and other sensory functions. They can gradually become isolated from other humans and the environment. A particularly devastating condition is age-related macular degeneration (AMD), which robs older people of their central vision. The macula is a specialized region of the retina having the highest density of photoreceptors. At its center is a small indented area, the fovea, which contains only cone photoreceptors and serves all of our high-acuity vision. We look at things we want to examine closely with that small region of the retina. There are only about 35,000 photoreceptors in the fovea, out of a total of 6 million cones in the entire human retina and perhaps 95 million rods, but if the foveal photoreceptors are lost, which happens in AMD, high-acuity vision is lost, and it is devastating for those affected. They cannot read, watch television, or do any of the things normally sighted people take for granted.

We know very little about AMD, what causes it or predisposes to it. The only environmental link known is smoking: Those who smoke have an increased risk of AMD. Some rare forms are inherited and those susceptible might get the disease at a young age. In one such form of macular degeneration, called Malattia Leventinese, the mutation has been identified in a gene coding for a secreted protein of unknown function. The mutation results in misfolding of the protein that causes it to be abnormally secreted and to accumulate both intracellularly and extra-cellularly.

This form of macular degeneration, then, has characteristics of other neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases in which excess accumulation of protein, either extracellularly or intracellularly, is the defining feature. However, for most cases of AMD, the link with genetics is tenuous. At present, there are no animal models of the disease, because relatively few animals have a fovea like ours. Higher primates, some birds, reptiles, and fish do, although the foveas of these latter animals are somewhat different. Thus, we can do relatively little for most cases of AMD at present and it severely compromises the quality of life of those who suffer from it. The same is true of those who become deaf in old age. They, too, can become quite isolated from their fellow humans.

An inherited retinal degeneration called retinitis pigmentosa (RP) is not a disease of the aged. Indeed, in most cases its onset is in the late teens or early twenties, progressing to complete blindness in the fifties, sixties, or even later. It is a fairly rare disease, affecting about one in 4,000 people worldwide. It is a disease of the rod photoreceptors, but cone photoreceptors are eventually affected as well. In contrast to AMD, where central vision is lost, RP begins in the periphery of the retina, gradually restricting the visual field. The fovea is the last to go, but eventually it, too, degenerates, leaving the individual completely blind. This disease has been studied intensively for more than 40 years and enormous progress has been made in understanding its causes. Furthermore, progress is being made with therapies for the disease, at least in treating animal models of the disease, of which there are many. Animals that have RP-like diseases include mice, rats, dogs, and cats.

RP, like many neurodegenerative diseases, was thought at one time to be a single disease with a single cause. We now realize that this is a very incorrect view. The first hint that RP represents several different diseases came from genetic studies. Careful analysis of patients and their families with RP first showed that about 50 percent of the RP cases could be linked to a genetic cause, but the genetics is varied. Sometimes the disease is inherited as an autosomal dominant disease—this means that the chances of an offspring having the disease are 50 percent; sometimes it is inherited as a recessive disease—if both parents have the mutant gene, one out of four children will inherit the gene.

There are also cases where the disease's inheritance is sex linked. The mutant gene is on the X chromosome, but females have two X chromosomes while males have just one. Males show the disease when the gene in their single X chromosome is defective; females need to have the defective gene in both of their X chromosomes. Therefore, males inherit the disease much more frequently than do females in these families. There are some even rarer inheritance patterns in RP, but they need not concern us here. Suffice it to say that the genetic variability is large, but there is much more to come.

Of the 50 percent of RP cases that can be linked to genetics, about 40 percent show an autosomal dominance inheritance. These cases were the first in which the specific genetic defect was discovered in the early 1990s by Thaddeus Dryja and Eliot Berson and their colleagues at the Massachusetts Eye and Ear Infirmary in Boston. They showed that a mutation affecting a single amino acid in the gene coding for rhodopsin (the protein that, when combined with a vitamin A derivative, is light sensitive and initiates vision) was the culprit in one family with RP. This discovery opened the floodgates and within a decade numerous mutations both in the rhodopsin gene and other genes found in photorecep-tor cells and important for initiating vision were discovered.

As of this writing (Fall, 2003) more than 100 different mutations in 35 different RP-causing genes have been found. In rhodopsin alone, more than 70 RP-causing mutations have been identified. Thus, RP is not a single disease, but more than 100 diseases, and this accounts for only about 60 percent of the cases of RP. The lesson here is that it is likely many of the neurodegenerative diseases will be as heterogeneous, and careful classification of them is critical if we are to deal with them. RP might be leading the way in this regard.

Figure 6-4 shows the rhodopsin protein, consisting of a chain of 348 amino acids, each indicated by a circle. The chain weaves in and out of the membrane seven times. The amino acids that, when altered, lead to RP are indicated in black.

At least 70 mutations in the rhodopsin molecule can lead to RP diseases. Some of the mutations lead to a misfolding of the protein, others to alterations in how the molecule is excited by light. Different mutations result in somewhat different diseases in terms of age of onset and progression of the disease, although there is considerable variability in people with the same mutation. This variability or penetrance is not well understood; as discussed in earlier chapters, both genetic and environmental factors could be involved.

With some understanding of the genetic basis of the autosomal dominant form of RP, investigators have turned to therapies and are focusing on two approaches: genetic and pharmaceutical.

FIGURE 6-4 A schematic drawing of the rhodopsin molecule. Amino acids which when altered as a result of a genetic mutation cause retinitis pigmentosa are indicated by black circles.

Gene therapy has already had spectacular success in a strain of dogs with one rare form of RP. These dogs have a defect in a gene that codes for a protein required to make the correct form of vitamin A to make rhodopsin light sensitive. A good gene is inserted into a virus that is then injected into the eye—into the subretinal space between the photoreceptors and the cells behind, the pigment epithelial cells. In this case, the defective protein is present in the pigment epithelial cells, but this is unimportant for the discussion; the defective protein could as well be in the photore-ceptors. The injected virus infects the pigment epithelial cells and the cells begin to make the normal protein—they now have the correct gene—and the dogs show a remarkable recovery. For any of this to happen requires, of course, exact knowledge of the mutated gene, a virus that readily infects the defective cells, and luck!

The second approach is via drug or chemical therapy, and several classes of compounds have been tried. Significant success has been obtained in animals with some forms of RP following the administration of growth factors such as the neurotrophins described in the beginning of Chapter 2. These molecules are important for the survival and growth of neurons in the developing brain, and they also seem to help defective cells from dying or, at the very least, they slow down the deterioration of genetically defective cells. All forms of RP might not respond to growth factors, and infusing the growth factors into the eye is a problem because these are proteins that must be put directly into the eye. That we have animal models with various forms of RP is important to this effort, and it is now possible to make mice with other forms of RP using transgenic techniques, thus providing the opportunity to test drugs on a wide variety of mutations that cause the disease.

Another substance that has been shown effective in RP is vitamin A. Initial studies with a population of human RP patients who had various forms of the disease suggested a very small but positive effect of vitamin A therapy. However, the effect was so minimal that many physicians felt it was not particularly useful. But as transgenic mouse models of various forms of RP have been developed and the specific genetic defects found in human patients are induced in them, it turns out that some types of RP are helped quite significantly by vitamin A, but others not at all.

The lesson here is that when seeking therapies for a disease, it is critical to know what specific form of the disease you are dealing with. A therapy might be very effective for one or a few forms of a disease, but ineffective for many or most forms. Thus, when testing a therapy on a population with various forms of a disease, the positive effects might be swamped out by the nonresponders. Thus, careful characterization of different forms of the neurodegenerative diseases is essential, and this classification is just beginning for many age-related neurodegenerative diseases such as AMD, Alzheimer's, and even perhaps Parkinson's disease.

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