A Cure for Wilson Disease? A World Expert Eyes Gene Therapy

Patients come to Michael Schilsky, MD, a Yale Medicine gastroenterologist and hepatologist, after struggling for years—sometimes decades—with a range of symptoms such as extreme fatigue, jaundice, personality changes, stutters, and movement issues (such as clumsy hands). The patients recount their experiences of being misdiagnosed and treated for the wrong condition or seeing multiple doctors but never getting answers.

One patient sought out Dr. Schilsky after a relative watched a medical mystery show on TV and identified his problem: Wilson disease, a genetic disorder in which excessive amounts of copper accumulate in the body, particularly in the liver and brain. It’s a condition most doctors rarely see, if at all, and might not be trained to recognize.

Dr. Schilsky is widely considered to be a world expert in Wilson disease. He is a prolific researcher who has published seminal papers about the disease and has for years helped write and update the clinical guidelines for Wilson disease from the American Association for the Study of Liver Diseases (AASLD), in addition to those for the European Association for Liver Disease (EALD).

He has served as chairman of the medical advisory committee of the Wilson Disease Association (WDA), a national organization, for years. At Yale, he built the Wilson Disease Program from the ground up and made it one of the WDA’s Centers of Excellence. Yale is one of just a handful of programs in the United States and abroad that offer comprehensive care for people with the condition. He’s working with other specialists to establish a multicenter registry to help gather information about the disease.

All this work is furthering Dr. Schilsky’s goal of learning as much as possible about Wilson disease—and raising awareness so that people who have it will be more likely to get an early diagnosis. “It is a great relief to a patient and their family, community, and supporters when they learn what their condition is and have new hope that they can improve,” he says.

Estimates of how many people have Wilson disease vary. A commonly reported figure is one in 30,000 people in the world, according to studies conducted before researchers discovered its genetic cause—any one of a number of possible mutations in the body’s ATP7B gene, which is involved in transporting copper in the body.

We spoke with Dr. Schilsky about his work and his longtime passion for finding new solutions for patients with Wilson disease.

Wilson disease interferes with the body’s ability to eliminate excess copper, which can spread to organs including the liver, brain, and eyes. This can cause life-threatening damage.

We consume copper in foods such as nuts, peanut butter, shellfish, mushrooms, whole grains, and chocolate. A small amount of this copper is essential to the body. For example, it supports enzymes that help the body metabolize iron and other elements that support body function. Too little copper is not good, and too much of it is toxic.

When the body is functioning normally, the copper you consume travels from the gut to the liver, which eliminates excess copper so that it doesn’t accumulate to a dangerous level. Some copper is released from the liver into the circulation and is distributed through the body to supply copper for copper-dependent enzymes. The excess copper passes into the bile (a digestive fluid) then out of the body in the stool.

A healthy ATP7B gene is important for removing excess copper from the body in the normal way. A pathogenic mutation in that gene interrupts the process, which leads to Wilson disease. A person inherits Wilson disease only if they inherit two ATP7B mutations, one from each parent (however, not everyone whose parents have defective genes will get the disease).

The condition is present at birth, but it doesn’t manifest until several years into life, and symptoms can take years or decades to progress from mild to severe. Early in life, Wilson disease may frequently be silent, although it may be diagnosed if it shows up on lab testing with abnormal liver tests. If it is more severe, jaundice may be an early symptom; later, when the disease moves to the brain, there may be neurological or psychiatric symptoms, affecting such functions as memory, impulse control, and judgment. Most symptomatic patients will eventually develop Kayser-Fleischer rings, which are copper deposits that are seen as copper-colored rings in the outer region of the cornea, a tell-tale sign that can be detected during an eye exam using a slit lamp.

I first encountered Wilson disease when I was a medical student at University of Chicago, working on a rotation in a medical ward. The patient was in his late 20s and was very sick with jaundice and ascites (fluid buildup in the belly); he was getting worse and worse, and had a failing liver that led to his death. Doctors diagnosed his Wilson disease during this hospitalization, but there was nothing we could do to help him because the disease had progressed too long without detection.

Fast-forward through my medical residency at Albert Einstein College of Medicine, when I had a ward rotation on the general clinical research center where I saw a number of these patients. Most were in much better condition than that first gentleman I had met, but they had more variations in the symptoms of their disease, including pediatric patients, mostly with liver disease, and older patients with neurological and mental health complications.

Later, as a fellow in gastrointestinal diseases, I spent time in research laboratories at the Albert Einstein College of Medicine in New York City. I worked with two scientists whom I would describe as luminaries in the field.

I remember sitting with one of these experts, who was a liver specialist, and saying, "Wilson disease is a rare disease. How am I ever going to learn about the rest of liver disease by studying this little pocket of interest?" He kind of smiled and said, "You will spend a lot of time figuring out what other liver diseases most of the patients who think they have Wilson disease have."

There is research underway into ways that we can detect the disease at the earliest time points, so that we will be less likely to see patients like the first one I met. There is one laboratory looking at a way to set up neonatal screening.

For now, people may undergo clinical and biochemical testing for Wilson disease if they have a family history of Wilson disease, unexplained liver disease, neurological or psychiatric disease with liver abnormalities, or are found to have Kayser-Fleischer rings. Genetic testing is also helping expand our diagnostic capabilities. If a patient’s initial tests suggest Wilson disease, genetic testing can identify which genetic variants a patient has. If they are found to have a mutation in the ATP7B gene, their first-degree family members (parents, siblings, and children) should be tested as well to see if they are affected and need treatment or if they are carriers.

We can’t cure Wilson disease, but we can treat it. We start with lifestyle management, such as a low-copper diet to limit additional buildup of the metal in the body. A healthy diet, exercise, maintaining a healthy weight, and avoiding alcohol are all important.

As far as medication, there are two ways to control the excess of copper that are Food and Drug Administration (FDA)-approved. The first is chelation therapy, in which small molecules bind to copper they find in the body and excrete most of it out in the urine. This includes D-penicillamine (distributed under the brand named including Cuprimine®, a capsule, and Depen®, a tablet), which was the first oral therapy developed for Wilson disease. Due to reactions to this medication, a second chelating agent, trientine, was developed and is an alternative treatment for this disorder.

Zinc acetate (sold in the U.S. as a capsule under the brand name Galzin™) is a maintenance treatment for patients who have already been treated with a chelating agent. It acts to block copper absorption in the intestinal tract and increase its excretion from the body.

These are reasonable tools that are helping people with Wilson disease. But we're still far from perfect. One issue is that therapy is lifelong, and there are significant problems with non-adherence to medication that have led to less than good results for some patients. Another problem is that these medicines need to be taken multiple times a day, and we know that adherence would go up dramatically if they were needed only once-a-day.

Patients also need to be monitored to make sure their medications are working properly and well; if not, they may need to have the dosages adjusted. There are also side effects. D-penicillamine, for example, can cause symptoms such as hypersensitivity with rash and fever, joint aches, loss of protein from the kidneys, and skin changes. Rarely muscle weakness can occur. Additionally, about 10% to 15% of patients who have neurological symptoms and who start on chelation therapy develop a paradoxical worsening of their neurological disease.

Even though we can control the disease with current treatments, it’s frustrating that we still can’t cure it. However, we are on the cusp of trying to cure Wilson disease by genetically modifying the liver so it can produce a protein that is missing in patients with Wilson disease. The ATP7B gene provides instructions for making this protein, a copper-transporting ATPase type 2, which functions as a pump that removes copper from the body via biliary excretion.

We give the patient an infusion that contains a sort of Trojan horse—a dead virus inside of which is a shortened version of the ATP7B gene that will fit inside the virus. The idea is that this “invader” will reach the liver cells, and the enclosed gene will initiate production of the protein that would normally restore proper copper metabolism. At this point, we are exploring this in clinical trials, and if this therapy is successful, a patient would ultimately be able to process copper normally, stop taking D-penicillamine, and eat a normal diet—chocolate and all.

Another exciting area of potential treatment advance is gene repair, and there are newer methodologies that may allow gene editing to fix the mutations in patients’ cells. By targeting the repair mechanism along with a proper template for the correction of the mutation to the liver, the process can potentially restore the function of the liver cells to handle copper properly.

There are 10 Wilson Disease Association Centers of Excellence in the U.S.—including our program at Yale—plus three more in Great Britain, Germany, and India. These centers have physicians who are well trained in the diagnosis and treatment of Wilson disease, and they offer the broad services needed by Wilson disease patients and their families. They perform research and train physicians. The concept was to create environments where we would not only care for patients but also be able to advance our knowledge about the disease.

We look at our program at Yale as kind of a hub-and-spoke system. Wilson disease affects multiple organ systems, so the latest guidelines emphasize treatment by a team. At Yale, people can be seen by dietitians, social workers, psychologists, psychiatrists, movement disorder specialists, adult and pediatric liver specialists, and liver transplant experts as necessary.

We work with local providers in places that don’t have the resources they need to offer the best care for Wilson disease patients. That way, our patients don't have to come to us as frequently, but they can get much of their care elsewhere and check in with us from time to time.

Sometimes I step back and find it amazing that I’ve had this area of focus for all these years. I can see that some things we once thought were very “black box”—that we didn’t understand at the time—line up in a way that is allowing us to more clearly see patterns and better understand Wilson disease.

We’ve had many successful outcomes. One patient, in particular, had developed bad tremors and was at one point hospitalized in a psychiatric ward. For the longest time, people didn't know what he had until imaging studies suggested that areas in his brain might be affected by a metabolic disease, and Wilson disease was considered. Once he was diagnosed, he joined one of our clinical trials and responded very well. Stories like that keep us motivated to do what we do.