This provocative title certainly got the attention of many of our patients. Like all brief news reports, it left out some key details. The findings are certainly exciting. Gene therapy is now a reality. The first ever trials in humans are for a form of blindness called Leber Congenital Amaurosis. Infants with this disease are born without a functioning retina and are either blind or low vision from birth. In a series of studies over the past decade, scientists have identified the causative defective gene, identified the same disease and gene in lab mice and Briard dogs, and shown that inserting the correct gene leads to recovery of vision. These successes in animals led to the first human trials by three separate research groups, two in the United States and one in England. Starting out with adults and gradually moving to younger patients, these trials have all shown that gene therapy for this disease appears safe, and all three have shown some recovery of vision in these adults. One group in Philadelphia headed by Jean Bennett and Albert Maguirre has reported on 12 patients who have shown no ill effects from the surgery over at least a one year interval. Each of the 12 patients reported improvement in their sight and showed measurable improvement on clinical tests of vision. The greatest improvement was observed in the youngest individuals, several of whom could use their vision to walk around for the first time.

The Fox article highlights findings of the second American group headed by Sam Jacobson and Art Cideciyan. Their work describes a patient who continued to improve over a year after the gene therapy. As with all patients, the corrective gene was placed away from the center of the retina (the fovea) to avoid damaging this sensitive area. As reported in the New England Journal of Medicine, this treated area of the retina became the preferred center of her vision rather than the usual fovea. The findings suggest that the patient’s brain rewired itself to utilize the treated region of the retina.

Patients (and parents) with Leber Congenital Amaurosis are understandably excited about the new possibilities this research opens up. But how widely can this approach be applied to other forms of retinal degenerative disease? What are the necessary steps that need to be taken before gene therapy can be applied to a particular disease?

1. The causative gene has to be identified. Much of our work with the Southwest Eye Registry involves working with families to identify a mutation. Even in a disease as rare as Leber Congenital Amaurosis, we now know of at least 10 genes that can cause blindness. Gene therapy is presently available for only one, the form of Leber caused by mutations in the RPE65 gene.
2. The mutation has to lead to loss of function. Some gene mutations cause damaging proteins to be formed. These are typically dominant negative mutations; dominant because they are inherited in an autosomal dominant manner and negative because they have a deleterious effect on the retina. This kind of mutation cannot presently be treated with gene therapy, although there are several promising avenues for research in this area. In most cases, diseases caused by loss of function are recessive. The patient inherits a bad copy of the gene from each parent and a critical protein is not produced. Gene therapy places a good copies of the gene in the retina so that the protein is again produced.
3. Blindness has to be due, at least in part, to a functional defect and not entirely to degeneration. Conditions like Leber Congenital Amaurosis initially show functional loss because a critical component of retinal chemistry is missing. Often it takes years for this defect to cause degeneration, the actual loss of retinal cells. Gene therapy is most effective in the early stages. A useful analogy might be running an engine without oil. The engine runs badly, but if oil is added, catastrophic damage to the engine can be averted.
4. Animal models for the mutation must exist so that appropriate doses and procedures can be developed.

So which conditions fit the above requirements? Which conditions are most likely to see gene therapy in the near future?

1. Other forms of Leber Congenital Amaurosis. Other genes within the visual cycle have be shown to cause Leber and are likely to cause functional defects that could be corrected with gene therapy.
2. Achromatopsia. Patients with monochromacy are born without functioning cones and have extremely low daytime vision. The genes causing these conditions have been identified and gene therapy has been successful in an animal model.
3. Stargardt disease. This is otherwise known as juvenile macula degeneration; i.e an inherited form of macular degeneration that affects children. The gene is known, the mutation leads to loss of function, function is typically lost before there is degeneration, and there is an appropriate animal model.
4. Recessive forms of retinitis pigmentosa and cone-rod dystrophy. Here the challenge has been to identify the disease-causing genes. This hunt will be the subject of upcoming articles.