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People born with ADOA (Autosomal Dominant Optic Atrophy) have vision loss that is not correctable with glasses. It can start early in life: 80% of patients have symptoms before age 10, most commonly between ages 4 and 6. Fading of color vision may be the first sign of the disorder. Over time, their vision gets gradually worse. By the time they’re teenagers, a noticeable area of grey or blurry vision may slowly expand in the center of their vision, and by middle age, that spot can grow so large that it cuts off their functional sight. The degree of vision loss that occurs can vary from person to person, however, and its extent remains difficult to predict. Some people may experience only limited sight defects, while others (up to 46%) can progress to legal blindness.

Although ADOA is a rare disease, it is the most common inherited optic nerve disorder seen in clinical practice. There are currently no treatments available to address the disease itself or prevent vision loss—instead, patients must cope with its symptoms through supportive services and low-vision aids. Recent developments in understanding how genes work, however, are offering hope. New methods of genetic medicine could potentially result in drugs that diminish ADOA’s impact, or in some cases, prevent it from developing at all. In this article, we’ll explore how the disease occurs, and why it has become a promising target for new approaches to treatment.

Root Cause for ADOA

ADOA is triggered by a mutation in a single gene called OPA1. This gene codes for a protein, also called OPA1, which is critical to every cell’s metabolism: without it, mitochondria (the “power plants” in a cell that provide it with energy) can’t fully function, and some types of cells may wither and die. The severity of the resulting disease—and its potential for treatment—depend largely on how that mutation occurs.

Inside our chromosomes lie two nearly identical strands of DNA, each of which contains a copy of the OPA1 gene. ADOA is typically caused by a mutation in one copy of OPA1. There are two types of ADOA. Approximately 20% of patients have “ADOA plus” syndrome. This more severe form of the disease is caused by a mutation in OPA1 that produces a toxic protein that can affect cells in the eye and elsewhere in the body. ADOA plus can have severe implications for hearing and the nervous system, as well as for muscles, including the eye muscles.

The more common form of the disease primarily affects nerves in the eye and can lead to long-term vision loss. In patients with this form of the disease, the mutated copy of the OPA1 gene does not produce any functional protein. The other copy of OPA1 still works and produces its share of the protein, but without both copies of the gene working, only half the necessary protein is produced. This phenomenon is known as a haploinsufficiency.

The reason that the haploinsufficient form of ADOA affects only a person’s vision is complicated. Each cell type may respond to the reduction of OPA1 protein in a different way. Retinal ganglia cells are the cells in the retina that send information from the eye to the brain. These cells carry massive amounts of visual information to our brains and require phenomenal amounts of energy—and if the amount of OPA1 protein they can express decreases, the mitochondria of those cells do not function as well as they should, producing less needed energy for the cell. This loss of normal proper mitochondrial function is thought to lead to impaired cell function and to cell loss.

Thanks to more widespread use of genetic testing and an increasing understanding of the role of OPA1 in causing ADOA, researchers are unlocking potential new approaches to treatment. One such example is the work being done at Stoke Therapeutics, where we are using fragments of RNA—called antisense oligonucleotides (ASOs)—to increase the RNA produced by the OPA1 gene. As a result, the non-mutated gene is coaxed to produce more protein than usual, thereby compensating for the mutated strand which does not produce proper protein. Using this method, we hope to boost OPA1 protein levels, which may restore function to the optic nerves, thereby slowing or even stopping vision loss from ADOA.

The Role of Natural History Studies in Genetic Medicine

The severity of ADOA symptoms and the rate at which they develop differ among patients: some people’s eyesight will deteriorate steadily over their entire lives, while others’ may stabilize for 15 to 20 years before declining once again. In order to create effective treatments in the future, it will be critical to understand how the disease progresses in a broad range of people.

This scenario is not limited to ADOA: as scientists and drug researchers uncover the root cause of more and more genetic diseases in the lab, it becomes increasingly important to understand how these disorders affect patients, sometimes in subtle ways. Natural history studies are an essential way to obtain important information so that we can understand diseases in much more detail than is usually measured in regular clinical practice. These studies, which follow a cohort of patients over time, let scientists and clinicians observe the long-term impact and progression of a disease, identify the problems that patients experience day-to-day, and focus research and treatment accordingly.

To that end, Stoke Therapeutics is now conducting FALCON, a natural history study of people living with ADOA. It will provide data that will inform future drug development. The study will enroll patients aged 8 to 60 and will examine them over time to map the eye damage, nerve function, and overall quality of life that occurs at different stages of the disease.

To do so, the study will use a variety of objective methods, like measuring retinal thickness using Optical Coherence Tomography (OCT) and recording activity in optic nerve cells with an electroretinogram, a device that can measure how optic nerves react to light stimulation. The study will also include traditional visual acuity tests and will track participants’ ability to see low-contrast images.

Going Beyond ADOA

Conducting a natural history of ADOA will do more than just record the progression of the disease. Once complete, it will provide a real-world baseline that researchers and clinicians can use to track how well a future therapy is working and will inform the timing of when that therapy needs to be given. The study may also provide data on how an intervention impacts the body, revealing whether it’s helping nerve cells in the eye work more effectively, or if it’s just stopping them from dying off.

This effort could result not only in better therapies for ADOA, but better treatments for retinal and optic nerve disorders in general. In conducting the study, researchers will help identify care centers around the nation that have the capacity to support patients with rare eye diseases and will help clinicians evaluate their current standard of care for those patients. In short, it is the first step towards potentially saving the sight of thousands of patients who suffer from an incurable disease.

Steven Gross, M.D., is an adult and pediatric neuro-ophthalmologist and Senior Medical Director at Stoke Therapeutics. At Stoke, Dr. Gross is the medical lead for the company’s ophthalmology clinical development program, which includes STK-002, a proprietary antisense oligonucleotide in preclinical development for the treatment of autosomal dominant optic atrophy (ADOA)