First administration of gene therapy clinical trial for Wilson’s Disease completed at YNHH
A new gene therapy for Wilson’s Disease hopes to provide patients with alleviation of severe symptoms associated with the condition.
Eric Wang, Senior Photographer
For decades, Wilson’s Disease has evaded comprehensive treatment. The wide-ranging physical and neurological symptoms of the condition have upended afflicted patients’ lives, with no potential cure in sight. However, a new clinical trial at Yale has provided one of the most effective treatments to date to control the disease and its symptoms and has the potential to alleviate some aspects of life with Wilson’s.
A groundbreaking new gene therapy clinical trial headed by Michael Schilsky — professor of medicine and medical director of adult liver transplant at Yale New Haven Transplantation Center — was administered to its first patient in the world at Yale New Haven Hospital.
The treatment aims to enable the patient’s body to produce the copper transporter protein that is missing in those with Wilson’s Disease — the absence of which causes toxic levels of accumulation of copper in the body. In fostering the presence of the protein, the hope is to alleviate some of the symptoms associated with Wilson’s Disease and empower the patient to be able to return to different physical and emotional aspects of their lives before their Wilson’s diagnosis.
“We have limited treatments for Wilson’s Disease … [that] are just to control the disease, not to cure the disease,” said Daksshi Hettiarachchi, primary care coordinator of the clinical trial. “If this gene therapy works, if they don’t have to take this [D-penicillamine] treatment, it’s going to be a huge, huge plus for them.”
A rare inherited condition, Wilson’s Disease is expressed at various levels from patient to patient. Symptoms include, but are not limited to, jaundice; Kayser-Fleischer rings, which are copper-toned rings in the eyes; speech and physical coordination problems; and fluid buildup in the legs and/or the abdomen.
Schilsky explained that the signs and symptoms of the disorder may be present in a patient for a long time, and the disorder is best treated when diagnosed early at a time of minimal to no symptoms. Upon diagnosis, he continued, patients may either feel relieved to learn the cause of their illness or undergo a life-changing reckoning if they experience disabling symptoms.
“Some of the physical impairments due to the neurologic expression of the disease may make work impossible and create difficulty with activities of daily living,” Schilsky said. “The mental health changes may cause disruption in relationships and isolation and even require hospitalization if severe.”
Due to the nature of the impact of Wilson’s Disease on patients’ personal lives, interest in conducting an increased number of new clinical trials to combat the symptoms and causes of Wilson’s has exploded over the past decade, according to Schilsky. He explained that novel treatment agents are not the only center of attention in this effort; previously-existing copper chelator treatments, such as choline tetrathiomolybdate and trientine tetrahydrochloride, are undergoing comparison testing to assess their effectiveness in combating Wilson’s and alleviating the deterioration of neurological disease seen in some patients whose symptoms unexpectedly worsen upon receiving treatment.
Schilsky said one standout example of this increased interest was found at the University of Navarra in Spain, where Gloria Gonzalez-Aseguinolaza, director of innovation and transfer at the university, and her colleagues were able to build and test a small construct of the Wilson’s Disease gene inside a viral vector, a tool used to deliver genetic material into the cell.
Desiring to support a gene therapy project, Schilsky spoke with colleagues who had heard of Gonzalez-Aseguinolaza’s work and wanted to bring it into clinical practice.
“My answer was yes, and I thought that since the disease has available treatments, the patient could be given the treatment and then assessed for its function before their standard of care treatment was withdrawn — making it safer for the patient,” Schilsky said.
Bringing and testing a Phase 1 clinical trial treatment at Yale necessitated the establishment of strict criteria for selecting which patient(s) could be viable candidates for the trial. According to Hettiarachchi, the rigorous screening process to ensure that the patient’s disease condition is stable takes about three months to complete before treatment can begin.
Upon passing the screening criteria, Hettiarachchi continued, the patients receive an IV treatment of the gene therapy, which goes into immediate effect.
“I think immediately, [the liver] starts to produce the copper transporter protein that we expected for the gene therapy to produce,” Hettiarachchi said. “And then we have a lot of frequent lab work to assess that the gene therapy is working, whether the protein is being produced […] After three months, we do a radio copper assessment on these patients. And then that’s where we definitely know whether the gene therapy is working.”
The timeframe for the entire clinical trial will likely take three to 10 years due to its dependence on the success of early Phase 2 treatments, according to Schilsky. He explained that one of the key components of the trial’s success is to see whether there is a dose response in human patients, as was observed in preclinical animal testing, and that the dose level is safe and effective during and following treatment.
Upon receiving the novel treatment, Warren — the Wilson’s Disease patient treated at Yale — has seen improvement in symptoms associated with the disorder and looks to return to a normal diet instead of the restrictive one that Wilson’s patients undertake due to complications associated with copper buildup in the body.
While the safe administration of the gene therapy and preliminary symptom alleviation seen in Warren is promising, Ricarda Tomlin, clinical research manager for the trial, noted that the same success needs to be seen in multiple patients to call the trial as a whole successful.
“A single treatment is not scientifically very convincing, and we don’t know if the treatment for Warren was successful yet or not, we just know it was safely administered,” Tomlin wrote in an email to the News. “The study needs to enroll 16 patients for this Phase 1/2 segment and follow them for a number of years, before we have enough data to call it a success.”
Tomlin noted that the trial is currently recruiting more patients at Yale and around the world, and that if overall success was observed in those 16 patients, the trial would enter Phase 3, after which the FDA would review it and determine whether it could be offered as a widespread medical treatment for Wilson’s Disease.
For those that may not see success following participation in the trial, Schilsky explained, future options include going back on the most common medication for Wilson’s Disease, D-penicillamine, and potentially gene repair or replacement via CRISPR-based technologies.
According to Hettiarachchi and Schilsky, as the only Center of Excellence for Wilson’s Disease in the Northeast, experienced adult and pediatric hematologists, neurologists, psychiatrists and transplant specialists can work with clinical researchers to apply their expansive banks of knowledge to developing and administering novel powerful treatments.
“Yale has a clinical trials unit dedicated to helping support the infrastructure to be able to do innovative treatments with close monitoring and obtaining the necessary biosamples that are inherently needed to measure safety and outcomes of treatments,” Schilsky said. “So yes, these partnerships are invaluable.”
Tomlin recognized the important contributions of many different departments at Yale in bringing this clinical trial together, including ophthalmology, neurology and MRI experts, Yale’s Positron Emission Tomography Center, YNHH’s investigational pharmacy, the Hospital Research unit, and members of the ethics boards.
She also emphasized their gratitude towards patients with conditions like Wilson’s who willingly participate in complex, time-intensive clinical studies to help the research team determine that the trial will be safe and efficient for everyone.
Wilson’s Disease occurs in about 1 in every 30,000 people.