Treatment for retinal dystrophies near fruition

By Roibeard O’hÉineacháin

GOTHENBURG — The day is fast approaching when sight-restoring treatment becomes available for patients with previously untreatable hereditary retinal disorders, a British ophthalmologist told the 7th International Conference on Low Vision.
“We do have the prospect of treatments currently being developed by many people. The task for clinicians is to be in a position to take full advantage of these treatment possibilities when they become a reality,” Alan Bird MD said.
Several biological approaches have shown great promise in recent years in animal trials in the treatment of retinal disorders similar to retinitis pigmentosa in humans.
The new treatment strategies include the use of growth factors, gene therapy and retinal transplantation. Human trials with these new forms of therapy are likely to begin within a few years, Dr Bird added.

The use of growth factors may represent the simplest of the biological approaches, he noted. The aim of this approach is to alter the metabolic environment of the retina to prevent the apoptosis, or programmed cell death, of photoreceptors of the diseased eye.
This cellular suicide is one of the body’s ways of discarding unwanted cells and preventing the production of abnormal cells. In eyes with retinal disorders, however, rampant apoptosis occurs in cells without any apparent defect.

Animal experiments now suggest that in eyes with hereditary retinal disorders, mutant retinal cells create a metabolic environment that induces the mass-suicide of photoreceptor cells by altering the secretion of growth factors.
To illustrate the principle, Dr Bird described the results obtained with a chimeric mouse in a study carried out by Vernon Huang and his associates.
The mouse was generated from the fusion of two embryos, one an otherwise normal albino mouse, and the other a mouse with a mutation of the gene for the photoreceptor molecule rhodopsin, which causes a type of retinitis pigmentosa.

The resulting mouse had roughly equal amounts of cells from the two embryos distributed throughout its body, including its retina.
Surprisingly, apoptosis occurred with the same frequency in retinal cells derived from the albino mouse as in those from the rhodopsin mutation mouse. They did find that the proportion of cells derived from one origin or the other in any particular patch of retinal tissue modified the speed of the progression.
“The investigators concluded that a cell that dies is no more likely to have the cell mutation than one that doesn’t. It is the presence of the mutant cells that causes cell death but it doesn’t determine which cell will die.

“This is a fundamental observation that cell death is induced by some sort of alteration of the metabolic environment of the retina. Therefore if you could modify the environment you could then slow down the rate of cell death,” Dr Bird explained.
Subsequent studies have shown that intravitreal injection of certain growth factors significantly reduces the rate of visual deterioration in animals with hereditary retinal disorders.

Among the problems that now remain before the approach can be used in humans is an improved delivery system for the growth factors. These may take the form of slow release physical devices or cell transplants.
In addition there are unanswered questions about the safety of growth factors when used in this way. They may influence cells that cause fibrosis and inflammation. In addition, it is not clear how long they will delay the disorders, he said.
Gene therapy is another approach to the treatment of retinal dystrophies which has made significant headway in recent years.

Depending on the nature of the mutation being treated, the aim of gene therapy is to either increase the production of an under-produced normal protein or block the production of an abnormal protein, Dr Bird said.
So far, scientists have overcome most of the obstacles which had originally confronted them in their early work.
They have now worked out ways to incorporate genes into retinal cells and cause them to function in such a way that they can restore vision to animals with hereditary retinal degenerations.

The first real evidence of therapeutic gain through gene therapy in retinal degenerative disorder came from a study published two years ago (Nature Genetics 2000 July; 25(3):306-10) by Robin Ali MD.
The study showed that intravitreal injection of adeno-associated viruses containing corrective genes for a specific retinal mutation in mice resulted in the anatomical and functional restoration of retinal structures.
“He was able to show that by gene therapy he can induce something to occur in the retina that was fundamentally different from what would have otherwise occurred. In fact, it induced a normal behavioural characteristic that otherwise would not have existed,” Dr Bird said.

The mice in the study were ‘RDS’ mice, which have a mutation in the gene that encodes for a photo-receptor-specific membrane glycoprotein, peripherin-2.
The protein is necessary for the stabilisation of the retina’s outer segment discs. In RDS mice, the mutation of the gene for the protein causes a photoreceptor dystrophy similar to retinitis pigmentosa in humans.
Dr Ali and his associates found that there was a re-establishment of the structural integrity of the photoreceptor layer of the retinal tissues with the newly incorporated genes.

Moreover, electro-retinograms showed a restoration in electrophysiological readings, with increased a-wave and b-wave amplitudes.
More recently, Gregory Acland MD at Cornell University announced that he was able to use the same approach to restore vision for several years in dogs with a mutation in the RPE65 gene (Nature Genetics 2000 May; 28, 92–95). In humans, mutations in the same gene cause early onset of retinitis pigmentosa.

“The anticipation is that retinitis pigmentosa in humans with mutations in this gene may be treated in the next three years or so. If that is successful, x-linked retinitis pigmentosa — which accounts for 85% of retinitis pigmentosa and for which a dog model exists — would be the logical next step,” Dr Bird said.
Scientists are also looking at gene therapy approaches to improve the “quality control” of protein synthesis in retinal degenerative disorders that result from the production of aberrant proteins.

One way to achieve that might be through the transfection to affected retinal cells with genes for catalytic oligoribonucleotides called hammerhead ribozymes.
These ribozymes occur in the ribosomes in the cell’s endoplasmic reticulum. They serve to distinguish between normal and aberrant messenger RNA, which transfers genetic information from the nuclear DNA to the macromolecular complex in the ribosomes where proteins are formed.

The ribozymes have two recognition sequences which are specific for a particular gene. If the incoming messenger RNA molecule has an incorrect sequence, the hammerhead ribozyme cleaves it in two, thereby preventing production of the aberrant protein.
Dr Matthew La Vail and his associates (Proc. Natl. Acad. Sci. USA, Vol. 97, Issue 21, 11488-11493, October 10, 2000) at the University of California in San Francisco were able to demonstrate that transfection with the genes for ribozymes targeted to a mutation that causes retinal dystrophies in humans significantly reduced retinal degeneration in rats genetically engineered to carry and express the gene. Moreover, it also improved the retina’s electrophysiological function.

“There are obviously many challenges left with gene therapy but many of them have been overcome. Efficient transfection has been achieved together with long-term appropriate expression and appropriate protein targeting. There may be safety issues but to date there is no evidence that gene therapy is harmful to the eye,” Dr Bird explained.

Dr Bird noted that the possibilities for treating hereditary retinal degenerative disorders are close to becoming a clinical reality. Soon in many patients retinal blindness will no longer represent the final defeat of ophthalmological science.
Ophthalmologists and low-vision specialists therefore will need to work together to ensure that patients receive sight-restoring treatments as soon as they become available.

“Many patients who attend low-vision clinics are no longer seeing ophthalmologists. With the prospect of treatment, it perhaps would be appropriate to recycle such patients into ophthalmic practice so they can be studied, their disease characterised and the causative genes identified.
“That way, when treatments become available in four to six years that patient population is known to the clinician and appropriate patients can be recruited,” Dr Bird pointed out.

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