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Retinitis Pigmentosa

NOTE 1: If you are unfamiliar with the anatomy of the eye, the structure of the retina and the functioning of the visual pathway, please visit: The Visual Pathway

NOTE 2 : In most cases, clicking on an image will enlarge that image thus showing more of its details

Introduction
Clinical Diagnosis
Modes of Inheritance
The Fundus of the Eye
Histological Studies
The Molecular Pathology of Retinitis Pigmentosa
Therapy
Conclusions
Acknowledgements
References

Introduction

Retinitis pigmentosa (RP) refers to a group of diseases that affect about 1.5 million or one in four thousand people around the world. Retinitis pigmentosa, as the name implies, is a disease of the retina but as we will see later it specifically affects the retinal rod photoreceptor cells.

Patients with RP do not show any systemic, metabolic, inflammatory, toxic, traumatic or dietary condition. (1.). However, 5% of patients have profound congenital deafness and a vestibular disorder (Usher syndrome type I), and 15% of patients have associated partial hearing loss (Usher syndrome type II or type III), and some rare forms of retinitis pigmentosa are associated with systemic neurological disease. These are:

In the past ophthalmologists believed that RP was caused by an inflamation of the retina, hence the name, Retinitis (compare pneumonitis in the reference to the inflamation of the lungs or peritonitis in thereference to the inflammation of the peritoneum, the lining of the abdominal cavity).

The word "pigmentosa" comes from the observations of the early ophthalmologists that black pigment could be seen on the retinas of RP patients when they looked into their eyes with their ophthalmoscopes (see Figure 5).

Although pigment does appear on the retinas of RP patients, the reference to retinitis as an indication of inflammation turned out to be a misnomer. The use of light microscopy, the advent of high resolution microscopy and, more importantly, the development of sophisticated biochemical and genetic techniques, led to the conclusion that the disease is due to degenerative changes within the visual cells of the retina, (see below).

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Clinical Diagnosis

Clinically, symptoms of retinitis pigmentosa include:(2.)

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Modes of Inheritance

Retinitis pigmentosa can be inherited as an autosomal dominant, as an autosomal recessive, or as an X-linked disease. In the X-linked disease, mothers are carriers and the males only of the family are affected while the female become carriers.

Some patients show RP only in one eye (see Figure 2), while in others Retinitis pigmentosa is associated with other diseases as part of a syndrome. In the vast majority of cases, the isolated or sporadic cases, a genetic link cannot be determined.

It is difficult to identify the relative frequency of different types of RP. The largest single group is the isolated or sporadic patients, usually comprising 40% - 50% of index cases. These might includes a sizable number of autosomal recessive patients.

Recently, a digenic mode of inheritance for RP was described. In this type of RP a combination of two loci was necessary to produce the clinical picture of RP.(3.)

Oligogenic forms of RP may not be uncommon but they are very hard to demonstrate.

Investigators at the Ottawa Eye Institute report a patient with an affected and a normal eye (Dr. S. Couupland, Personal Communication)(see Figure 2).

Generally, the dominant type of the disease is the most benign form of RP, while the X-linked type of the disease is the most virulent. Patients with The recessive type of disease start having problems with their vision by the fifth decade of life.

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The Fundus of the Eye

Normally, the fundus shows a uniform pink color with a Optic disc (yellow disc) through which the arteries and veins seen on the surface of the retina, enter and leave, respectively (see Figure 3).

Fundus of a Normal EyeClick Here to see details of the image

Figure 3. - The fundus of a normal Eye. Note the uniform pink color of the fundus and the yellow color of the optic disc. The arteries, which supply nutrition to, and veins, that remove metabolites from, the inner retina, traverse the fundus and enter and exit the eye through the optic disc (Original slide courtsey of Dr. Gilles Desroches, Ottawa, Ontario.

In the early stages of Retinitis pigmentosa, black "bone spicules" appear on the surface of the retina, the blood vessels become narrower than normal and the optic disc adopts a waxy appearance (Figure 4).

The Fundus of a patient with Early RPClick Here to see enlarged image

Figure 4 - The Fundus of a patient with early RP. Note the waxy appearance of the optic disc, the narrowed blood vessels and the black spots ("bone spicules") at the periphery of the photograph. (Original slide courtesy of Dr. Gilles Desroches, Ottawa, Ontario).

As the disease progresses the black spots, increase in number and eventually coalesce (Figure 5) to form blind spots in the visual fields where the patient cannot see.

The fundus of an advanced case of RP RetinaClick Here to see details of the image

Figure 5 - The Fundus of an advanced case of an RP retina. Note the numerous accumulations of black spots on the fundus.

In some patients, only one eye is affected while the other eye remains normal (see Figure 2).

Ophthalmologists chart the progress of these coalesced pigment granules by means of a Visual Field Chart in order to follow the progress of the patients visual ability.

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Histological Studies

Typically the RP patient experiences difficulty seeing under dim light conditions (nyctalopia) as a young adult, followed by progressive loss of both rod and cone vision over the ensuing years to decades.

Immunocytochemical studies using anti-rhodopsin antibodies, revealed shortening of their outer segments of the rods, usually beginning in the mid peripheral retina and progressing with time to involve the macula and far periphery.

Rod cell degeneration is followed by changes inthe adjoining cones, including shortening of their outer segments, and ultimately, cone cell death and blindness.

Additionally, microscopic examination of retinas obtained from human subjects with advanced retinitis pigsmentosa, revealed the absence of rod cells and the presence of ultrastructural abnormalities in both the retinal pigment epithelial cells and the few surviving cone cells. The inner retina appeared to have been unaffected.

The disease in the human retinas examined were was too advanced to allow for the assignment of a primary site for retinitis pigmentosa in the retina. However, the absence of rods in the tissues examined and the fact that the first clinical observation in retinitis pigmentosa is the onset of night blindness supported the suggestion that the disease primarily affects these photoreceptor cells.

This suggestion was enforced by the finding that animals (mice, rats, cats, dogs and pigs) showing electroretinographic changes similar to retinitis pigmentosa, were found to have changes in their photoreceptors similar to those found in RP, namely, degeneration of the photoreceptor cells and eventual loss of the retinal photoreceptor layer (compare Figures 6 and 7).

However, different species of animals exhibited different modes of photoreceptor degeneration. In some, animals degeneration occurred at the time of cell differentiation (some types of mice), others showed changes at the time of the development of the outer segments (Royal College of Surgeons or RCS rats), while still others showed degeneration after the cells have reached full length.

The fact that human subjects with RP continue to have useful vision into their second and later decades of life would suggest that retinal degeneration in these subjects would belong to the second or third categories of degeneration.

A light microscope section of a normal retinaClick here to see details of the image.

Figure 6: shows a microscopic picture of a section of a normal retina. The retinal Pigment Epithelium layer, the photoreceptor outer segment layer, the outer nuclear layer, the Outer Plexiform Layer and the inner Nuclear layer are shown.

Microscopic section of an RCS (degenerated) rat retinaClick here to see details of the image.

Figure 7 - A degenerated section of an RCS rat retina. Note the complete absence of the photoreceptor layer including the outer nuclear layer.

To understand why black spots appear on the surgace of the retina of RP patients we can take our clue from the findings that the eyes of patients examined showed ultrastructural abnormalities in their pigment epithelial cells. Since we cannot follow the progress of the black spots seen on the fundus of human subjects investigators resorted to the study of animals exhibiting retinal degeneration.

These studies included the protein metabolism in the photoreceptor cells of the so-called Royal College of Surgeons (RCS), which showed that the pigment epithelium plays an important role in the maintenance of the normal length of the outer segments of these cells (See The Visual Pathway for details of the biosynthesis, maintenance and shedding of rod outer segment disc membranes under normal conditions).

Briefly, ROS disc proteins are synthesized in the inner photoreceptor segments and transported to the base of the outer segment where they are formed into discs. The older discs are pushed to the top of the outer photoreceptor segments where they are eventually shed and phagocytized by the RPE.

In the RCS rat The process of phagocytosis by the retinal pigment epithelium seems to fail In the early stages of the development of the visual cell outer segments. The uniform stack-like arrangement of discs in the outer segmnents is disrupted and disc debris starts to accumulate between the tips of the photoreceptor outer segments and the pigment epithelial cell layer.

Pigmented cells from the pigment epithelium invade the layer of debris and starts to remove the debris and the degenerated photoreceptor cells. This process might coincide with the first appearance of the black spots or "bone spicules" on the retinas of patients afflicted with Retinitis pigmentosa.

AS more photoreceptor cells degenerate, the layer of debris increases in thickness and the pigmented cells entering the area of the photoreceptor layer increases presumably to remove the degenerated cells.

The retina becomes thinner and more black spots appear on the fundus as observed by the ophthalmoscope. These spots become larger as the black spots coalesce. Thus, the migration of retinal pigment cells into the area of the degenerated human photoreceptor cells might explain the appearance of the black spots on the fundus of the RP patients.

Why is there a failure of the phagocytic process in RP?

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The Molecular Pathology of Retinitis Pigmentosa

The causes of retinal degeneration in retinitis pigmentosa are not yet known. Defects in genes encoding for proteins and enzymes of the photoreceptor outer segments and those involved in the transport of vitamin A from and to the outer segments of the photoreceptors have been found in patients presenting with RP and RP-like symptoms.

Although the list of gene defects associated with RP is rapidly expanding, it is not however, known how any of the mutations lead to photoreceptor dysfunction and death.

Three different suggestions, based on experimental results, were presented to explain degeneration in retinal dystrophies (4.)

A. Mutations in genes encoding the Structural Proteins of rod outer Segments

Mutations in the opsin and peripherin/RDS genes have been reported in association with changes in the ROS of some animals and in patients presenting with Autosomal Dominant Retinitis pigmentosa.

Mutations in the Opsin Molecule:

Investigations using molecular genetic techniques, have found more than 100 mutations or small deletions in the opsin molecule of patients presenting with autosomal dominant RP. These mutations cause addition or deletions in the opsin amino acid chain ranging from position 17 in the amino terminal of rhodopsin to the penultimate position 347 at the carboxyl terminus.

Mutations in the opsin molecule might affect the normal folding of the molecule, or its capacity to bind vitamin A.

The large number of mutations in the rhodopsin gene might reflect some of the extensive clinical variability among patients with autosomal dominant RP.

Rhodopsin mutations that cause Autosomal Recessive RP are very infrequent: However, a patient, from a consanguineous marriage, was found to be homozygous for a mutation in the rhodopsin gene that caused a premature termination of the transcription of the gene. This resulted in the complete absence of functional protein.(5.)

Another recessive mutation was observed in a different family from consangnineous origin, segregating in a a mutation that changes a single codon in the rhodopsin gene. The authors concluded that the resulting rhodopsin was unable to activate transducin.(4.)

Mutations in Peripherin/Retinal Degeneration Slow (Peripherin/RDS) gene Mutations in the peripherin/RDS protein was originally found in the RDS (Retinal Degeneration Slow) mouse.

The mutation in the pripherin/RDS protein was found to be caused by a large insertion in the peripherin/RDS gene which interferes with the transcription and translational processes so that no protein will be synthesized. As a result, mice homozygous for the mutation completely lack peripherin/RDS and develop no outer segments.

On the other hand heterozygous mice, which have a reduced concentration of peripherin/RDS, outer segments were present in normal numbers but were shortened and displayed structural disorganization. The retinas of these mice degenerated slowly with time. These finding clearly demonstrating the importance of the peripherin/RDS protein in the development and structural integrity of the ROS

In humans, there is extensive phenotypic variation among individuals heterozygous for the peripherin/RDS gene . Affected individuals display either a autosomal dominant RP pattern, dystrophy of the RPE, or cone and cone-rod dystrophies. These phenotypes all result from the degeneration of photoreceptors, but differ in the extent of rod and/or cone involvement.

It is possible that insufficient periphein/RDS leads to instability of the ROS and affects the continuous internalization and degradation of outer segment disc membranes by the RPE. This poses a substantial burden on the metabolism of the RPE cell leading to their atrophy, and the degeneration of overlying photoreceptor cells.

Mutations in the Rod Outer Segment protein 1 (ROM 1)

The ROM1 protein is present in rods and absent from cones. As ROM 1 normally interacts with peripherin/RDS it would be expected that mutations in the ROM 1 gene would cause phenotypes similar to those observed for peripherin/RDS mutations. However, gene mutations alone in the ROM1 protein did not seem to cause disease

Digenic Retinitis Pigmentosa

Exceptions to the reports which indicate that mutations in the ROM 1 gene does not cause retinal degeneration are found in cases in which mutations in bothe the peripherin/RDS and the ROM 1 genes occur simultaneously to form the "Digenic RP".

In all cases of digenic RP the mutations in the peripherin/RDS gene occurred at one locus whereas three different ROM1 mutations were identified in the families TESTED. Mutations in both the genes for the peripherin/RDS and one of these ROM1 mutations must be present in order to lead to retinal disease.

The RP phenotype observed in digenic RP probably results from defective development or shedding of the outer segments.

Patients of digenic RP present as psuedodominant RP. Carriers of the digenic disease have a 25% chance of transmitting the mutant peripherin/RDS and the ROM1 gene to his/her offspring.

How do mutations in the structural proteins of the rod outer segments lead to photoreceptor degeneration in RP?

It was suggested that the mutations in the genes encoding the outer segment structural proteins opsin, peripherin/RDS and ROM1would result in:

It was explained these accumulations of these proteins would disrupt the formation of the outer ROD rod outer segment discs thus leading to the shortening and disruption of the structure, of the rod outer segments.

On the other hand, mutations that prevent the phagotosis of outer segmemt discs by the RPE, would cause accumulation of ROS disc debris between the photoreceptor cells and the RPE. This would interfere with the normal passage of metabolites betweenn the outer segments and the RPE leading to the disruption the normal functioning of both the RPE and thephotoreceptor cells.

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B. The Phototransduction Cascade

Note: If you are not familiar with the details of the Phototransduction Cascade, please visit: The Visual Pathway

Presented below is a simplified flowchart of the Phototransduction Cascade including the proteins and enzymes in this reaction

The visual pigment, rhodopsin, makes up 85 % of the proteins of the photoreceptor outer segments. It consists of two different molecules:

When light enters the eye it is absorbed by rhodopsin leading to a a conformational change in the structure of rhodopsin and the isomerization of its vitamin a from 11-cis retinal to all-trans retinal.

The altered form of rhodopsin, Metarhodopsin II, is a chemically active protein which reacts and activates another protein, transducin (a protein which consists of 3 polypeptides: alpha, beta and gamma polypeptides) combined with the dinucleotide, GDP. Activation of transducin causes the separation of the transducin alpha polypeptide from the beta and gamma chains and the exchange of the GDP bound to the alpha chain for GTP.

Transducin alpha.GTP in turn activates the enzyme cyclic guanosine monophosphate phosphdiesterase, a protein which consists of 4 polypeptides: alpha, beta and two gamma polypeptides.

This activation leads to the release of the two gamma polypeptides from the PDE and the hydrolysis of the GTP which is bound to the alpha polypeptide of transducin, to GDP. This releases the transducin-alpha.GDP to recombine with transducin-beta-gamma polypeptides.

The activated PDE then hydrolyzes cyclic guanosine monophosphate (cGMP).

cGMP plays a very important role in vision. Under normal dark conditions of illumination, cGMP keeps certain channels called "cGMP-gated channels", located in the outer segment cell membranes open. These channels allow sodium and calcium ions to enter the photoreceptor cell.

Sodium ions are costantly removed from the outer segments by travelling to the inner segments where they are extruded by a sodium-potassium-activated enzye. Some sodium are also removed from the outer segment by exchange with a calcium/sodium exchanger located in the outer segment cell membrane.

Calcium ions are constantly removed from the outer segments by the sodium/calcium ion exchanger mentioned above.

Exposure to light, causes the activation of cGMP-PDE and the hydrolysis of cGMP. This leads to the closure of the cGMP-gated channels thus blocking the entrance of sodium and calcium ions into the ROS.

Calcium however keeps going out of the outer segments via the sodium/calcium exchanger. This leads to a decrease in the concentration of calcium in the outer segments, a condition which activates the enzyme, guanylate cyclase whose activity leads to the formation of cGMP, thus increasing the concentration of cGMP within the photoreceptor outer segments and opening the cGMP-gated channels.

The central role of the Phototransduction Cascade in vision and its location in the outer segments, would make a mutation in one of the genes coding the the proteins, including the enzymes, involved in the phototransduction cascade prime suspects in the development of Retinitis pigmentosa.

A defect in any one of these proteins or enzymes would cause adisruption of the phototransduction cascade and lead to similar phenotypic results.(see Ref.4.)

1. Mutation in the opsin gene

The first protein in the cascade is Rhodopsin (opsin + 11-cis-retinal).

Mutations in the opsin Gene are usually found in patients with autosomal dominant retinitis pigmentosa. However, reports of Autosomal Recessive RP was reported to have a mutation in the opsin gene which produce a markedly truncated odopsin molecules that would be functionally inactive because of the absence of the sixth and seventh transmembrane domains, including the 11 -cis-retinal attachment site.

2. Mutations in cGMP Phosphodiesterase

Some patients suffering from autosomal recessive RP were found to have mutations in the genes encoding the alpha- and beta-sub- units of cGMP PDE. These mutations would cause inactivity of the cGMP PDE. thus leading to the accumulation of high concentrations of cGMP in the ROS and the permanent opening of the cGMP gated cation channels.

These patients are night blind from birth and suffer from a progressive constriction of the visual field.

A similar mutation in the gene encoding the beta subunit of cGMP PDE of the rd/rd mouse (retinal degeneration mouse) , a phenotype with retinal degeneration similar to that in humans is observed. In mice homozygous for the gene demonstrate severe degeneration of photoreceptor cells which is directly or indirectly triggered by the rise in cGMP concentration.

3.Mutations in the cGMP-gated Cation Channel

The rod cGMP-gated cation channel is composed of three subunits (alpha beta and gamma). Five different mutations in the gene encoding the alpha-subunit have been reported in patients with autosomal recessive RP These mutations were found to either abolish the synthesis of the cGMP-gated cation channel protein or result in the synthesis of an abnormal protein.

Experiments with cultured transfected cells suggests that the mutant channel proteins fail to reach the plasma membrane and are trapped within the cell.

The absence of the cGMP-gated cation channels in the the rod plasma membrane will prevent sodium and calcium ions from entering the ROS thus leading to abnormally low sodium and calcium concentration in the cell.

Low calcium concentration in the ROS will activate retinal rod guanylate cyclase, and lead to a high rate of cGMP synthesis and its accumulation in the ROS. This would resemble the condition found in the mutations for cGMP PDE where the cGMP PDE is inactive leading to an accumulation of cGMP in the ROS.

C. Metabolism of Vitamin A in the Eye

Please refer to: The Visual Pathway for more details about the metabolism of Vitamin A in the Eye.

The outer segments, of course, contain millions of rhodopsin molecules but, to keep the process of vision going, two processes must occur:

1. the active Metarhodopin II must be reined-in and converted to rhodopsin in order to receive another photon of light.

This is accomplished by phosphorylation and reaction with the protein Arrestin to form Arrestin- Metarhodopsin II-phosphate. This reaction is followed by the release of all-trans retinal and opsin-phosphate from the arrestin-Metarhodopsin-phosphate complex.

Opsin-phosphate is dephosphorylated by opsin phosphatase to prepare it for combination with 11-cis retinal.

2. all-trans retinal must be re-isomerized to 11-cis retinal in order to combine with opsin to form rhodopsin.

This is accomplished by transporting the released all-trans retinal (see above) to the RPE whwer it is re-isomerized to 11-cis retinal and sent back to the ROS for recombination with opsin.

Vitamin A deficiency resulting from malnutrition or metabolic disorders results in a phenotype similar to RP.

Characteristically, symptoms of vitamin A deficiency include:

Lasting retinol (vitamin A) deficiency ultimately leads to photoreceptor degeneration in both humans and animals.

Mmutations in two protins located in the pigment epithelium, have been found in patients with equal rod and cone degeneration,

These patients exhibited deposits in the retinal pigment epithelium similar to the deposits found in the eyes of patients with vitamin A deficiency.

1. Cellular Retinaldehyde-Binding Protein (CRalBP)

The CRalBP is found in the RPE It acts as a substrate-carrier protein for 11-cis-retinol and 11-cis-retinal, thereby modulating the interaction between this protein and visual cycle enzymes.

Patients carrying the mutant gene express:

This mutation probably disturbs or even completely blocks the regeneration of 11-cis -retinal and hence the regeneration of rhodopsin.

2. Retinal Pigment Epithelium Protein 65 (RPE65)

RPE65 is a protein that is exclusively found in the RPE and makes up about 10% of its protein content. Its exact function is not known, although it is supposed to be part of the metabolism of vitamin A because it is associated with the plasma retinol-binding protein, 11-cis -retinol dehydrogenase, and a third unknown protein.

Reports of mutations in the RPE65 gene resulting in an autosomal recessive retinal degeneration have been reported in a number of families. Phenotypes varied from severe, early-onset RP to the syndrome of Leber's congenital amaurosis.

All of these mutations are likely to result in a partial or complete loss of function of the RPE65 protein, thus blocking the regeneration of 11-cis retinal and the formation of rhodopsin, which is required for visual function.

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Therapy

To-date only some rare forms of retinitis pigmentosa associated with systemic neurological disease are now amenable to treatment, namely (1a.):

1. Bassen-Kornzweig disease: is an autosomal recessive disorder characterized by a defect in the ability to secrete certain lipoproteins and a marked decrease in The absorption and transport of cholesterol, fats, and fat-soluble vitamins from the small intestine to the plasma and lymph. As a result, serum and, subsequently, tissues levels of cholesterol and trigylcerides are low.

In addition to systemic neurogical disorders starting in childhood, patients report decreased night vision and show the fundus changes typical of retinitis pigmentosa. Deficiencies of vitamin A and vitamin E are thought to be causative of the retinal and neurological degeneration.

It was reported that treatment with large doses of vitamin A in the early stages of the disease can result in restoration of retinal function within 24 hours. But a combination therapy of vitamin A and vitamin E was found to be required to slow the course of retinal degeneration over the long term. Advanced cases are not amenable to treatment, as a result of the large loss of photoreceptor cells. The neurological and muscular sequelae are also slowed with vitamin supplementation.

2. Friedreich-like ataxia with retinitis pigmentosa: patients showing symptoms of this disease present with a sharp decrease in serum vitamin E level. and show a thymine-to-guanine transversion at nucleotide position 303 in the alpha-TTP cDNA.

Patients with this disease are treated with daily doses of vitamin E leading to normalized serum vitamin E levels, and the stabilization of visual and neurological signs and symptoms.

3.classic Refsum's disease): In this disease, mutations in the gene encoding a peroxisomal enzyme phytanoyl-CoA alpha-hydroxylase result in the inability to alpha-oxidize phytanic acid. Thus leading to the accummulation of the acid in many tissues.

The onset of the disease is variable, with some patients presenting in early childhood and others in the second or third decade, with neurological symptoms occurring prior to the onset of visual symptoms.

Treatment involves:

small amounts of chlorophyll-containing foods may be returned to the diet after serum levels have been reduced to normal levels.

Favorable response to treatment has been observed in patients treated with the above mentioned regimen for four years, with stabilization of the retinal degeneration and appreciable improvement of neurological and dermatological disease.

To date, there is no effective treatment to influence the eventual outcome of common forms of RP. However, it has been reported that a daily dose of 15,000 units of retinyl palmitate (Vitamin A) slows the course of the disease in patients suffering from RP and Usher Syndrome. Vitamin E, on the other hand, may have a detrimental effect on retinal degeneration ( 13 )

Experiments with mouse models of autosomal dominant RP exhibiting a mutation in the rhodopsin gene at the threonine-17 : methionine in the opsin gene showed that vitamin A administration reduced the rate of decline of the electroretinogram and protected against photoreceptor rod outer segment loss.(12.)

On the other hand, vitamin A palmitate had no effect on the decline of the electroretinogram of transgenic mouse models of autosomal dominant RP carrying the opsin gene mutation in the proline-347 : serine(13), thus suggesting that the vitamin is selective in its effect.(12.)

, thus suggesting that not all of thecommon forms of RP will respond to treatment with vitamin A palmitate.

During the past decades, numerous experiments on humans, and animals carrying mutations analogous to those in human RP, have been performed to better understand the degeneration and cell loss in RP.

Among the various procedures used were:

Retinal Transplantation

Micro-aggregate suspension or intact sheets of human fetal retina were introduced between the neurosensory retina and the retinal pigment epithelium of human subjects.

The results indicated, at best and depending on the age of the patient, either subjective or objective improved light sensitivity during the initial period of the transplantation. This "improvement" disappeared 3 to 13 months later (6,7.).

Modification of mutant gene products

Proteins are synthesized according to a code that is copied from genes by a molecule called messenger ribonucleic acid (mRNA). The latter is synthesized with additional nucleotides that are later trimmed to normal size by enzymes, called ribozymes.

A mutation in a gene for a particular protein would cause the synthesis of an abnormal mRNA which cannot be trimmed to size by ribozymes thus resulting in the synthesis of an abnormal (mutant) protein.

Ribozymes engineered to cleave mutant mRNA to an mRNA that would produce a normal opsin molecule, were delivered to the retinas of transgenic rat model of autosomal dominant RP. The results indicated a considerable decrease in the rate of photoreceptor degeneration in these rats for at least three months post-operatively.(8.,9.)

It thus appears that delivery of ribozymes to the photoreceptors, has broad potential for more applied therapeutic purposes especially since efficient mutation-independent delivery systems targeting rhodopsin and peripherin have been developnt. This prediction is encouraged by the availability of animal models ranging from mice to pigs which are being used as experimental models.

The application of growth factors and/or pharmacological agents.

Repeated injection of the human Ciliary Neutrophic Factor (CNTF) analogue, Axokine, into the intravitreal space of cats suffering from the autosomal dominant model of rod-cone dystrophy, delays photoreceptor loss in this hereditary retinal degenerative disease(10.).

The rds/rds mouse exhibits a mutation in the peripherin/RDS gene, which is linked to many forms of dominantly inherited retinal degenerations in humans. Injection of CNTF ribozyme into the eyes of the rds/rds mouse, reduces photoreceptor loss, causes a significant increase in the length ofphotoreceptor segments, and results in a redistribution and an increase in the retinal content of the photopigment rhodopsin.(11.)

These effects are accompanied by a significant increase in the amplitude of the a- and b-waves of the electroretinogram indicating an improved response of the retina to light.(11.)

The above results would suggest that delivery of the CNTF ribozyme could potentially be useful in the treatment of some forms of retinal degeneration

Calcium Channel Blockers

rd/rd mice, are one of the animal models of autosomal recessive RP. They exhibit a deficiency in cGMP phosphodiesterase which leads to a large increase in the level of cGMP in photoreceptors. This increase is thought to lead to photoreceptor death, as a result of the continuous opening of the cGMP-gated channels.

Administration of the calcium-channel blocker, Diltiazem (usually used for the treatment of hypertension), to rd/rd mice, slowed the loss of photoreceptor cells in these mice.(15.)

Calcium-ion channel blockers have not yet been tried on human subjects suffering from autosomal recessive RP.

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Conclusions

In his 1993 Friedenwald Award Lecture (2.) ( a prestigius award for investigators in the field of Ophthalmology) , Elliot Berson, a leading investigator in the field of retinal degeneration, concluded that:

"Much work remains to be done. It still is my belief, as it was 20 years ago, that coordinated progams of clinical and basic research offer the best hope of finding treatments for patients with this group of diseases".

Both clinical and basic research on the causes of retinal degeneration and for finding therapies for the disease is ongoing. The development of new technics and the availability of animal models or retinal degeneration bode well for finding methods of amelioration or even treatment or retinal degenerations.

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Acknowledgements

I am indebted to Mme Helene Dussiaume for invaluable assistance in searching for references and making them available to me.

Dr. Gilles Desroches, Ottawa, Ontario and and Dr. S. Coupland, Ottawa Eye Institute, Ottawa University, Ottawa, Ontario, Contributed valuable illustrations for this Page.

References

1. Massof, R., Finkelstein, D., and Boughman, J. A.: Birth Defects, Orig. Artic. Ser. 18(6), 161 - 166, 1982

1a. Grant, Calvin A. M.D.; Berson, Eliot L. M.D. Int Ophthalmol Clin, Volume 41(1).January 2001.103-110

2. Berson, EL: Invest. Ophthalmol. Vis. Sci. 34: 1659, 1993

3. Kajiwara, K., Berson, EL and Dryja, TP: Science 264: 1604, 1994

4. van Soest, S. et al.: Surv. Ophthalmol. 43:321, 1999

5. Rosenfeld, JR, Cowley, GS, McGee, TL, et al: Nat. Genet. 1:209-213, 1992

6. Radtke, ND, Aramant, RB, Seiler, M, Petry, HM: Am. J. Ophthalmol. : 128 (3): 384-387, 1999

7. Ali, RR, Sarra, GM, Stephens, C,: Nat. Genet. 25 (3): 306-310, 2000

8. [published erratum appears in Nat Med 1998 Sep;4(9): 1081 ] Lewin, AS, Drenser, KA, Hauswirth, WW: Nat. Med. 4 (8): 967 - 971, 1998

9.Kumaramanickavel, G, Maw, M, Denton, MJ, et al.: Nat. Genet. 8: 10 - 11, 1994

10. Chong, NH, Alexander, RA, Waters, L, et al: Invest. Ophthalmol. Vis. Sci. 40 (6): 1298 - 1305, 1999

11. Cayouette, M, Behn, D, Sendtner, M, et al. : J. Neurosci. 18 (22): 9282-9293, 1998

12. Li, T, Sandberg, MA, Pawlyk, BS,: Proc. Natl. Acad. Sci. U.S.A. 1998 : 95 (20): 11933 -11938, 1998

13.Berson, EL, Rosner, B, Sandberg, MA, et al.: Arch. Ophthalmol. 111: 761 - 772, 1993

14.Sibulesky, L, Hayes, KC, Pronczuk, A et al.: Am. J. Clin. Nutr. 69: 656 - 663, 1999

15.Frasson, M, Sahel, JA, Fabre, M, et al. Nature Med. 5: 1183 - 1187, 1999

This page is still under construction and will be updated regularly. Please visit often and send me your comments and suggestions: HERE

P.S. I will be grateful to you if you can provide me with any human material to illustrate the various aspects of Retinitis pigmentosa.

Updated Thursday, September 25, 2003

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