There is no cure for the degenerative eye disease, Stargardt's dystrophy. Now, new gene therapies are offering a flicker of hope, and South Africa is involved in the research. Every now and again a newspaper headline proclaims the imminent cure of a disease that was once thought incurable. Sadly though, the optimism is usually found to be misguided, as the so-called cure unravels under closer scrutiny.

In learning to deal with an incurable disease, one learns not to invest too much in the hope for a cure.

Approximately 3000 South Africans suffer from the as yet incurable genetic eye condition known as Stargardt's dystrophy. And, with DNA screening underway with the eye on a possible gene therapy trial, a faint flicker of hope is emerging.

What is Stargardt's dystrophy?

People with Stargardt's experience a loss of central vision starting from anything between the ages of five and 20. Usually this means that they cannot read normal text, struggle to recognise faces, and will never be able to legally drive a car. The loss of sight is permanent, and at present there is no proven treatment to prevent or cure the disease. Neither does it help to wear glasses.

Even though it usually leads to legal blindness, most sufferers retain a significant amount of peripheral vision (what you see out of the corner of your eye).

The ABCR gene

Stargardt's dystrophy is what is known as an orphan disease. Only about one in 10 000 people are afflicted with it, and as a result the funding channelled toward Stargardt's research simply cannot compare with that spend on more mainstream diseases such as cancer and diabetes. Yet, with advances in genetics and high expectations of gene therapies, Stargardt's, due to it's genetic makeup, may be one of the first to benefit.

In 1997 a breakthrough study identified mutations in the ABCR gene (situated on chromosome 1) as the cause of Stargardt's disease.

The mutations result in an inadequate expression of the ABCA4 protein involved in the transport of energy to photoreceptor cells. Accordingly, a build-up of lipofuscin is observed in the retinal pigment epithelium (RPE - the "nurse" layer of cells underneath the photoreceptors.), thus inhibiting the RPE's ability to nourish photoreceptor cells.

As a result, these photoreceptor cells degrade, resulting in the loss of central vision.

This discovery finally gave researchers something at which to aim - if they could fix the genetic flaw, or somehow stop the build-up of lipofuscin, they would, in all likelihood, stop the degeneration of photoreceptor cells, and in doing so, prevent any further vision loss.

Analysing DNA

With trials aimed at fixing the genetic flaw expected to start within two to three years, the patient action group Retina South Africa is funding agene tracking project at the University of Cape Town to identify the precise genetic mutations causing Stargardt Dystrophy in South African patients.

Blood samples are sent to the university for DNA extraction and storage in their DNA bank. The DNA samples are then sent to Estonia where they will be analysed for variations in the ABCR (ABCA4) gene using a specially designed microarray chip.

The lab has been set-up in Estonia due to the burgeoning reputation of the country's biotech industry and comparatively low costs.

A microarray chip has all the genetic mutations of a single condition stored on the chip. A single DNA sample is run over the chip and the specific mutations are activated. This screening can do in a few hours what previously took months and years of analyses by traditional means.

Gene therapy trial

The first human gene therapy trial for Stargardt's is expected to begin within two to three years. The screenings organised by Retina SA are aimed at screening three hundred South Africans for possible participation in this trial.

Stargardt's disease is an autosomal recessive condition. This means that you can only get the disease if you inherit the Stargardt's gene from both your parents. It requires a double copy of the gene for the disease to be expressed.

Thus in a recessive condition like Stargardts the aim of gene therapy will not be to replace a defective gene, but simply to introduce a good copy of the gene, which would theoretically deliver the correct genetic information that the cell needs to produce the ABCR protein.

Thus, by means of an adeno-associated virus, scientists plan to sneak the corrected gene into affected cells, where they hope it will fix the genetic flaw and cure the disease.

Success in animal models

Gene therapy tests in a mouse model for Stargardts at Columbia University, USA, is showing great promise. "The gene reached the photoreceptors and was effective for a long period of time" said Stephen Rose of the Foundation Fighting Blindness, who sponsored the research. The gene was delivered via a lento virus, a man-made virus specifically designed to deliver genetic information to a targeted cell.

Studies on larger animals are needed before human trials can begin.

If successful, gene therapy would prevent the further degradation of photoreceptors in people with Stargardt's. Whether there may be an improvement in vision is, however, still unknown.

In a gene therapy trial in Dogs affected by Leber Congenital Amauroses their sight did actually improve. A human LCA gene therapy trial will begin in America very soon and what researchers learn from this trial will hopefully help in the treatment of other conditions, such as Stargardt Dystrophy.

Reasons for optimism

According to Claudette Medefindt from Retina SA, there are four reasons for optimism concerning the anticipated gene therapy trial:

• Stargardt's is a recessively inherited condition. This means that rather than replacing genes, the aim would be simply to introduce a new gene.
• Stargardt's has been successfully treated in mice.
• Stargardt Dystrophy is diagnosed in very young people where gene therapy would be most effective.
• The Microarray chip allows for rapid screening to find suitable patients for clinical trials.

Hope is a dangerous thing

Impressive as all this sounds, many, even more promising, treatments have failed to pan out. When suffering from an incurable disease, a good dose of scepticism is needed to keep things in perspective. Imagining what it would be like to have normal vision may be fun for a while, but will soon leave you guttered.

To quote the American writer Stephen King, who reportedly also suffers from Stargardt's, "hope is a dangerous thing. Hope can drive a man insane". And, to base too much hope on something with as little success in humans such as gene therapy may be little more than setting yourself up for disappointment.

On the other hand, when one considers the enormous scope of the research project, the blood samples being flown halfway around the world, the journal articles being published, and above all, the researchers devoting their careers to the search for a cure, one feels almost guilty not to hope.

So, out of respect one may keep an open mind and hope that all that effort does indeed bear fruit. Yet, in the interest of self-preservation, one might take a step back and say, "I'll believe it when I see it." - (Marcus Low, Health24)

November 2005