Céline Dion stands alone as a singer, a chart-topping ballad-belter who recorded some of the most iconic songs of all time, including “My Heart Will Go On” from the “Titanic” soundtrack. But, in 2022, Dion made headlines not for her one-in-a-million voice, but for a one-in-a-million diagnosis: a rare neurological disease called stiff-person syndrome (SPS).
Two years on, Dion has staged a “comeback” with the release of a documentary about her health struggles and a widely praised performance to close out the 2024 Paris Olympics opening ceremony last month. But with stiff-person syndrome, looks—and even the name of the disease itself—can be deceiving.
“I was so happy for her that she was able to do that,” Tara Zier, founder and CEO of the Stiff Person Syndrome Research Foundation (SPSRF), told Fierce Biotech in an interview. “Does that mean she's cured? No. Does that mean she's OK? No.”
A mild name like “stiff-person syndrome” belies the seriousness of the disease, a rare autoimmune neurological disorder that can upend patients’ lives with its broad range of symptoms. Stiffness is a symptom, but so are muscle spasms that can be triggered by emotional distress or environmental stimuli. As Zier explained, “Light touch or a loud noise can set off a full body spasm, and [patients] can freeze like a statue and fall.”
Throughout the disease’s progression, patients can struggle with walking and everyday movements, and they also commonly experience depression, anxiety and agoraphobia.
As a rare, underdiagnosed disease, SPS is not well understood and currently has no cure. But, in the wake of Dion’s diagnosis, that may finally be changing. Zier’s organization is now working to put together a registry and natural history study of patients living with SPS to facilitate thorough research. And cell therapy biotech Kyverna Therapeutics recently received an FDA designation to test a cell therapy in patients with SPS.
“The fact that people are researching it, the fact that we're getting therapies into clinical trials, it's definitely exciting,” Zier said.
Even before being diagnosed with SPS, Zier was intimately familiar with the discipline and hard work it takes to cure a rare disease. She was a practicing dentist and third-degree black belt in karate when her husband passed away in 2014. Her own health soon began to spiral, and she developed worsening symptoms of shortness of breath, fatigue, severe pain and difficulty eating.
“In 2017, I wasn't able to work, drive, care for myself or my kids,” Zier said, noting that it took years for her to finally receive a diagnosis of stiff-person syndrome. “People just don't know about it, and it's often misdiagnosed.”
She founded the SPSRF in 2019 to raise awareness and funds for more research into the disease.
“Not all neurologists are familiar with this disease, and so patients go through this diagnostic journey,” Amanda Piquet, M.D., told Fierce Biotech.
Piquet is a specialist in autoimmune neurological diseases at the University of Colorado Anschutz Medical Campus and is the physician who diagnosed Dion with SPS. In an epidemiology study of the disease currently under review, Piquet and colleagues found diagnosis typically takes more than four years, with the average across other studies being about seven years.
“It's reported even up to 19 years in prior literature,” she said. “Some people can go a very long time suffering before they get to the diagnosis.”
One hurdle patients face is the lack of international consensus on diagnostic criteria for the disease, something both Zier and Piquet, who is on the medical advisory board of the SPSRF, are working to address. One critical test, which is what ultimately confirmed Zier’s diagnosis, is for GAD65 antibodies in the blood and spinal fluid.
GAD65 antibodies are pumped out by malfunctioning B cells and disrupt a form of the glutamate decarboxylase enzyme. This enzyme plays a key role in making gamma aminobutyric acid (GABA), which is a critical neurotransmitter that inhibits the nervous system.
“The way I like to explain it in layman terms with patients is that you have a difficult time putting the brakes on the nervous system,” Piquet said. “You are constantly on the gas pedal.”
Normally, GABA would prevent your body from overreacting to mild stimuli like a sudden noise. But with GAD65 antibodies gumming up the works, the excitatory part of the nervous system charges forth unimpeded, leading to seizing and spasms.
“In terms of the underlying pathophysiology of the disease, there's still many things that need to be explored,” Piquet said. “However, our thinking of the disease is that this is really a hyper-excitability of the nervous system.”
With B cells thought to be the underlying culprit, that makes SPS a prime candidate for cell therapies.
“What you're seeing in the [chimeric antigen receptor T cell] space is we've now got very, very effective mechanisms to target certain types of cell lines,” said Sham Dholakia, M.D., Ph.D., head of rare disease at Kyverna Therapeutics, a clinical-stage biotech focused on cell therapies for autoimmune diseases.
“CAR T [cells] have really shown a lot of efficacy in the oncology space, and Kyverna’s vision is to use that science and amplify that in the autoimmune disease space, where the disease is a problem being driven by these aberrant B cells that are causing mischief,” Dholakia told Fierce Biotech.
By gene editing T cells so that they target the mischievous B cells manufacturing GAD65 antibodies, Kyverna hopes to develop the first-ever treatment for SPS. Their drug candidate, KYV-101, is set to enter a phase 2 trial that aims to enroll about 25 patients and dose the first of them by Dec. 31, Dholakia said.
The drug showed its potential in a case report published in the Proceedings of the National Academy of Sciences journal in June, where a 69-year-old patient with SPS showed less muscle stiffness and dramatically improved mobility after receiving an infusion of the CAR T cells. KYV-101 recently received a regenerative medicine advanced therapy designation from the FDA for use in the disease.
“What this means is that, potentially, there's an accelerated approval path based on the data that will be generated through this study,” Dholakia said.
The cells used in the drug were first developed and tested in B-cell lymphoma by the NIH.
Zier is excited about KYV-101’s potential, but sees it as just the first step in the march toward a cure.
“It's almost like the start of things, like 101, first day of school,” she said. “If it's not this therapy, maybe it's another therapy.”
For Zier, the lack of data and research on SPS is the biggest barrier to a cure. The SPSRF is spearheading an effort, in collaboration with Piquet and others, to create an international patient registry that will “follow patients over time and get the data we need for research,” per Zier. The group has designed a protocol and survey questions to ask the SPSRF’s global patient network, with the resulting data to be hosted by the National Organization for Rare Disorders.
With the registry and the research that uses it, as well as the in-progress consensus on diagnostic criteria, Zier is hoping to nail down the basics of a disease that has caused consternation among patients and physicians alike since it was first described in 1956. And though Zier, Piquet and others have been working for years to find a cure, there’s a certain Canadian singer who deserves some credit, too.
“She propelled us, like, 50 years with awareness,” Zier said. “We want to focus our efforts. We want to get to a better treatment. Education, awareness—Céline has played a huge part in that.”