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Cracking Peanuts and the Code to Wilson Disease

February 21, 2023
by Jeanna Lucci-Canapari

As a minister, Warren’s voice was his livelihood, but his battle with Wilson Disease has kept him from his calling. Through a Yale clinical trial he is regaining his voice, and sharing his story with others, to spread awareness about Wilson Disease, and sing the praises of participation in clinical research that has the potential to change lives.

Warren B. is the first person in the world to receive a groundbreaking treatment for this rare, serious genetic condition in which excessive amounts of copper accumulates in the body, particularly in the liver and brain. Wilson Disease can cause liver and neurological damage, as well as psychiatric issues with memory, impulse control, and anger. A strong, long-term relationship between Warren and Professor of Medicine Michael Schilsky, MD, the physician who is investigating this treatment, has been essential to this novel treatment which has the potential to help patients all over the world.

While Wilson Disease is rare, with one in 30,000 people affected, awareness is growing. That is in no small part due to Dr. Schilsky’s groundbreaking research; he is a world-renowned expert on Wilson Disease, and has published several noteworthy papers on the subject, and made significant contributions to the protocols that govern how the disease is diagnosed and treated.

The current regimen for Wilson Disease is the drug D-penicillamine, which Warren takes now, and has taken since his diagnosis in 1980 at the age of seven. Though D-penicillamine was the first oral drug developed for Wilson disease in the 1960’s, it is still an important treatment option for many patients. D-penicillamine is effective in replacing the mechanism in the liver that removes excess copper from the body so it can be eliminated from the body through the urine. To counter the effects of Wilson Disease, Warren also maintains a low-copper diet: no nuts, shellfish, chocolate, or mushrooms.

D-penicillamine can cause serious side effects, including initial worsening of neurologic disease that may cause longer-term neurological problems. Patients who are diagnosed with end-stage liver disease as adults, unlike Warren whose disease was found early, may end up requiring liver transplants for survival.

“With current treatments, we can control the disease, but we can’t cure it,” says Dr. Schilsky. His clinical trial uses gene therapy to genetically modify the liver so it begins producing the missing agent, a protein that functions as a copper pump to remove copper from the body. The patient receives an infusion consisting of a dead virus which acts like a “Trojan horse,” enclosing in itself a mini-version of the normal gene for Wilson Disease. The “Trojan horse” is delivered via the bloodstream to liver cells, where the enclosed gene will initiate production of the normal protein to restore proper copper metabolism. If the therapy is successful, a patient would ultimately be able to process copper normally, and would be able to stop penicillamine and eat a normal diet, chocolate and all.

“We have great partners in this trial who are interested in doing this the right way,” says Dr. Schilsky. “We don’t want to be just the first; we want to learn from what we are doing and continue to evolve and improve.”

Warren has been a patient of Dr. Schilsky’s for more than a decade, traveling regularly from his home in Harrisburg, Pennsylvania, to see him for his care. “I would not have participated in this study with anyone but Dr. Schilsky,” says Warren. “He is not going to put me in any kind of danger, so I trust him completely, and I have built that trust with him over the years that I have seen him. I know he has my best interest in mind so I felt comfortable because he would not have recommended it if my body couldn’t handle it medically.”

The Wilson Disease journey that led him to New Haven and the clinical trial has not been easy for Warren. He was first brought to his local pediatrician in Raleigh, North Carolina, by his parents because he was constantly tired. Seven-year-old boys are not known for being sedate; they have boundless energy and are always on the go. “For a seven-year-old to come home from school and take a nap, then go to bed right after dinner, that is very atypical,” he says. His pediatrician referred him to the Pediatrics department at University of North Carolina (UNC) Medical Center in Chapel Hill.

By sheer coincidence, the pediatrician Warren saw at UNC had recently read about this rare disease in a medical journal, and followed up on his suspicion. He ruled out other conditions that could cause severe fatigue, such as spinal meningitis and chronic mononucleosis, and noted he did not have the tremors and nerve conditions common in older Wilson patients. Then he checked Warren’s eyes. He discovered a tell-tale sign of Wilson Disease: copper-colored rings in the outer region of the cornea around his irises, known as Kayser-Fleisher rings. A blood test showing a low level of a copper protein, ceruloplasmin, confirmed the diagnosis, and Warren began taking penicillamine.

Despite the challenges of Wilson Disease, Warren was able to live a normal life, participating in school and athletics, and though he had some undiagnosed learning disabilities because of neurological damage from his Wilson disease, he was able to graduate from college and divinity school and become an ordained pastor in the United Methodist Church.

After he got married and moved to Pennsylvania, and after doing so well for so many years, his local physician decided to revisit his penicillamine regimen, and cut his dose in half. This had an upside for Warren, who then took fewer pills each day, and reduced the cost of this expensive medication. He remained on this lowered dose for ten years.

But the challenges of the disease returned when he had what appeared to be a seizure, and went to the emergency room. “During a period of work stress,” he recalls, “I woke up in the night. I could not remember my name, where I was, or who my wife was.”

At the emergency room, his memory began to return. It was there that he saw his first specialist: a neurologist. After his seizure, Warren’s memory returned, but he developed tremors and a stutter, like many long-term Wilson patients. He also suffered a traumatic decline in his motor skills: he could no longer type or play guitar; he began physical therapy. His neurologist prescribed clonazepam to help with his tremors. When she felt she had taken him as far as she could, she referred him to Schilsky.

“Dr. Schilsky said, ‘I can’t promise it’s going to get any better,’” recalls. “but I can promise it is not going to get any worse.” The first issue Dr. Schilsky addressed was the likely cause of his episode: Warren’s reduced dose of penicillamine. Schilsky promptly returned him to his original dose.

“The key was understanding where things may have not gone right before and putting him back on course,” Schilsky says. “And it takes a village, as they say. We needed people from different disciplines: mental health, neurological expertise and liver care. I was cautiously optimistic we would make progress, and he was someone who was great to work with.” Schilsky found Warren to be a very engaging patient. who still partook in a wide range of activities despite his illness, such as hiking on the Appalachian Trail; he was also very well read.

It was also important, says Schilsky, not to minimize the effect Wilson Disease was having on Warren’s life. “From his marriage, to his work, to what his future would look like,” he says,
“it alters their perception of themselves. You start with someone who is a gifted speaker, who then has trouble with his speech. Getting to know him a little bit was very important.” Schilsky has published results from a registry study based at Yale demonstrating that major depressive disorder is a common problem among Wilson Disease patients. Warren began seeing a counselor in coordination with Dr. Schilsky, to help him address the emotional and psychological challenges of his disease. He had to make hard decision to go on full-time disability from the job that he loved. But on the upside, he became a stay-at-home Dad to his daughter, while his wife, also a United Methodist minister, continued to work.

While the disease is clearly genetic, its clinical expression in each individual can depend on other factors, such as the environment, and the patient’s ability to cope with inflammatory injury. More than 500 mutations are associated with the disease, and two are needed to cause it: one from each parent, on each allele. “It is known as a disease that has a very wide range of clinical expression,” Schilsky says. “Generally, the liver is affected first, and the neurological and psychological impact typically occurs much later, but that is not always the case.”

Though he had been diagnosed with Wilson Disease, Warren’s participation in the clinical trial. was not a given. He had to meet strict qualifications confirming two mutations. One of the mutations was unclear, so a liver biopsy was performed which found high levels of copper and confirmed the diagnosis.

“The biopsy made him eligible,” says Schilsky. But if the two mutations could have been identified without doubts, “he would have been treated a year earlier.” Still, there is a bright side to this delay: finding another way to confirm eligibility allowed for the participation of more patients due to changes in the study protocol allowing participation of patients like Warren, where there was controversy about whether one of the mutations was pathogenic or not. “It’s a rare disease so there is a limited amount of data. We had to let the protocol catch up to the thinking.”

Warren had his first injection under the care of Schilsky and his team at Yale in December, and for him, it was a positive experience. “Every patient that goes into a study gets that extra eye on them, extra care,” says Schilsky.

At the beginning of Warren’s important participation in this research, it is still unclear how much he will improve, and whether it has the capacity to diminish his set-in symptoms. Since he began participating in trials at Yale six years ago, Dr. Schilsky is happy to see that his symptoms have improved. He still cannot type, and must remain on anti-tremor medication, but is able tackle and take pleasure in the intricate needlework of counter cross-stitch.

Today, Warren remains on full-time disability because of the neurological damage he has suffered, but still maintains his connection with his church, and continues his life’s mission to reach out and help others. “God called me and has me here for a purpose, and this is my purpose,” Warren says. “I can help other patients in the future. I would love to give him a retirement gift of never having to do another transplant because this study works.”

For Schilsky, while the results of the study remain to be seen, there is already an upside. “Anything we do in the space of Wilson Disease raises awareness, which helps people look for diagnosis earlier when patients are not as affected with the copper overload. The earlier, the better, and then the treatment is preventive for developing complications.”

As he began his new treatment, Dr. Schilsky asked Warren the first food he will have, once he no longer has to restrict his diet.

“Well, you won’t let me drink,” he replied. “but my father passed away at age 52. Growing up there was a local baseball team, the Durham Bulls, in triple A. My father and I would go to the game and we would get a drink and a bag of peanuts in the shell, and sit at the ball game and crack the peanuts. It’s a wonderful memory. I want to go to a ball game and get a bag of peanuts. I don’t care who’s playing, a little league game for all I care. To sit at a game in the summer and have a bag of peanuts.”

Submitted by Lisa Brophy on February 21, 2023