The loss of vision is one of the hardest things to witness in the clinic. Children with FD can see, but as they enter their teens, their vision starts to deteriorate, and by early adulthood many patients are legally blind.

The eye is a very complicated organ. We used to blame the blindness on scarring of the corneas, but over the years, we have discovered that patients with FD are actually losing the cells at the back part of the eye, an area known as the retina. The retina is a bundle of light sensing neurons that eventually come together to form the optic nerve and travel  towards the brain’s visual cortex. The brain puts together this incoming information to interpret contrasts, colors, depths, textures and create our visual world. As the neuropathy advances and the retina starts to become damaged, visual perception becomes impacted. For patients with FD this starts with, perhaps, having more difficultly at night when the light is low, progressing to the point where they need large print, or in some cases can no longer see beyond a few meters and can only read by pressing their eye up to the page.

For years, scientist at the Center have been scanning the retina of patients with FD. Within minutes of entering the clinic, patients have the back of their eye imaged down to almost the cellular level. Hundreds of patients have been scanned year after year. To really understand what is happening in the eye, the Center has partnered with top neuro-opthalmologist Dr. Gadi Wollstein, who  joined NYU and works on eye diseases. Dr. Wollstein and his team began mining the data to look for patterns. After several meetings, the eye started to look like a real target for testing new therapies. When it comes to FD, there are certain static neurological characteristics of the disease that are developmental, meaning the nerves fail to survive development and the problem is there from birth. Then there are other characteristics that are neurodegenerative, meaning the cells start off functioning but progressively die overtime. This was the story that began to emerge for the eye.

With statistical analysis there was a very clear pattern. The youngest patients with FD to undergo retinal imaging were 5 years old. Already their retinas were thinner, but the cells were there, which meant that they had survived development. But as the patients came back each year, their retinas began to thin. By their early 20s, most patients had reached a point where they had already lost a substantial amount of retina neurons and plateaued.

The rapid rate of decline by early adulthood resembles patient stories about the impact loss of vision. For the team it presented an important endpoint to consider for the clinical development plan. The retina has what is known as a “window of opportunity,” a time to intervene to save the existing cells from dying, and slow neurodegeneration. When it comes to finding disease-modifying strategies, what are needed are endpoints like this that can reliably and quickly track whether a treatment is working. Now we know the natural history of the progression, we can start to direct ways to try and slow the trajectory of the nerve cell loss. It is possible we will need another approach to replace the nerves in adults. This is why we are lucky to have a diverse scientific advisory board with different ideas for different stages of the disease. We have to be open to different ideas and potentially combining treatments.

Right now, the retina has become an active area of research in FD. The work led by Dr. Frances Lefcort linking the defective elongator protein to developmental and neurodegenerative functions was published in Nature. It showed the retinal cells survive, but their mitochondrial machinery is disrupted, and the cells begin to degenerate. Together with Dr. Elisabetta Morini in the laboratory of Sue Slaugenhaupt they were awarded a highly competitive grant to create models FD to test potential treatments. The grant award to Dr. Lefcort and Dr. Morini is a real stepping stone along the path to developing new therapies for FD. It’s brings together two excellent laboratories and scientists with a track record of successful discoveries in a highly collaborative project, which will no doubt move the science forward.

The eye data becomes part of the natural history study, which makes it quite powerful as a clinical end point. To change the sight of a person with FD would be an important breakthrough in medicine. For patients, sight loss limits their lives a lot or becomes another hurdle that can make their world smaller. What emerges from this collaborative effort is a path forward, with the basic science and clinical medicine moving together. That is an important step. We have a target of nerves to save at the back of the eye.

Funding: Familial Dysautonomia Foundation, National Institutes of Health (R 01), The Michael J Fox Foundation