Natalie Stack was only two months old when she had surgery to remove a liver tumor. When the tumor turned out to be benign, her family breathed a sigh of relief.
But a few weeks later, Natalie’s mom, Nancy, noticed that her infant daughter still had urinary issues. They went back to a kidney specialist near their home in Orange County, and he was the first to suspect that Natalie had a rare disease called cystinosis.
“And he said ‘if she does have this, you’re in luck — Dr. Jerry Schneider down at UC San Diego Health is the guru of this disease,’” Nancy said. “That’s how we ended up seeing the doctors here for the past 25 years.”
Cystinosis affects just 2,000 children and young adults in the world, including 500 in the United States — and Schneider eventually determined that Natalie just happens to be one of them.
As the Stack family came to learn, cystinosis is caused by an inherited mutation in the gene that encodes the protein cystinosin. As a result, the body doesn’t produce cystinosin and can’t break down the amino acid cystine. Over the years, cystine crystals build up and damage various cells and organs, including the kidneys, liver, muscles, white blood cells, eyes and central nervous system. Children with cystinosis typically reach kidney failure by about nine years old, requiring kidney dialysis or transplantation for survival.
A drug called cysteamine — first studied by Schneider at UC San Diego in the 1970s — slows the progression of cystinosis by removing excess cystine, but it’s not a cure. For those who make it into adulthood, the average lifespan is still around 27 years old. What’s more, cysteamine is a terrible-tasting medication with side effects that include vomiting and diarrhea — and it must be taken every six hours for life. Along with multiple other necessary medications, kids with cystinosis typically take 50 drug doses per day.
Natalie Stack tells her story.
“We would have to wake Natalie up at 11 p.m. and 5 a.m. every single night,” Nancy said. “Some nights when she was a child, she’d be kicking and screaming and we’d have to force her to take the medication. It was miserable, but we saw it as our job. There just wasn’t a choice.”
A birthday to remember
In 2003, on the eve of her 12th birthday, Natalie wrote a wish in purple crayon on a restaurant napkin — to have my disease go away forever.
Those heartbreaking words inspired Nancy and her husband, Jeff, to launch the Cystinosis Research Foundation with the goal of funding research and the development of new treatments for cystinosis, and ultimately to find a cure. Since its inception, the Cystinosis Research Foundation has raised $35 million for scientific studies into the cause and treatments of the disease, supporting 143 studies in 12 countries.
Over the years, the Cystinosis Research Foundation has awarded UC San Diego a total of more than $5.2 million in research funding. With this support, Schneider, now professor emeritus, and Ranjan Dohil, MD, UC San Diego School of Medicine clinical professor and pediatric gastroenterologist at Rady Children’s Hospital-San Diego, developed a slow-release version of cysteamine. This newly improved medication was approved by the FDA in 2013 and is currently available for patients as Procysbi™. Cystinosis patients can now take their cysteamine every 12 hours instead of every six.
“Natalie was part of the clinical trial for delayed-release cysteamine, the prototype for what is now Procysbi,” Nancy said. “And it was the first time in her entire life that she got a full, uninterrupted night of sleep. That’s huge.”
The Cystinosis Research Foundation is not just a funding agency, it has also become a close community of patients and their families.
“It’s amazing to me that when this small group of people decides they want to do something, it gets done,” said David Clarke, whose nine-year-old son, Joshua, has cystinosis.
Experimental stem cell therapy
Now, the Stacks, Clarkes and other cystinosis families are hoping for even better treatment options, and perhaps even a cure. To this end, the Cystinosis Research Foundation has funded the work of
Stephanie Cherqui, PhD, associate professor of pediatrics at UC San Diego School of Medicine, since 2012.
“Dr. Cherqui is the rock star of our community,” Nancy said. “She cares deeply about the patients and is always available to talk, to explain her work and to give us hope. She said years ago that she would never give up until she found the cure — and now we are closer than ever before.”
Cherqui’s team is excited about a new potential approach to treating cystinosis — with autologous stem cell transplantation. In this procedure, hematopoietic stem cells (blood cell precursors) are removed from a patient and re-engineered in the lab using gene therapy techniques to carry the missing cystinosin. Then the cells are returned back to the same patient. These stem cells act as vehicles that carry the corrected gene to every tissue of the body.
“We were completely amazed when we tried this approach in the mouse model of cystinosis — autologous stem cell transplantation completely reversed the disease. All of the tissues are saved, even the kidneys,” Cherqui said.
Now Cherqui’s team is working with the Food and Drug Administration (FDA) to test the safety of this treatment in humans — the last requirement before they can begin a Phase I clinical trial. To help advance this research, cystinosis patients, including Natalie and Joshua, frequently donate their blood.
“These patients are amazing — they travel to our lab again and again to have blood drawn for our research, even though they are not sure they will benefit from this treatment. They are paying it forward for others with cystinosis,” Cherqui said. “Yes, we have to be cautious, but I do think it’s time for hope. If this approach works as well in humans as it does in mice, a one-time stem cell treatment could last a lifetime, possibly eliminating vision problems, endocrine complications and the need for kidney transplantation — and the never-ending cycle of medications. This could also be a proof-of-concept for the treatment of other degenerative disorders that affect multiple organ systems.”
“The Cystinosis Research Foundation and all of the scientists and doctors they’ve funded have decided they want to find a cure — and it finally feels like we may be getting close,” said David Clarke.
It takes a village
Cherqui’s pre-clinical studies have been possible because of the continued support from the Cystinosis Research Foundation and the National Institutes of Health. The Cystinosis Research Foundation’s latest award to Cherqui, and a $5.2 million grant she recently received from the California Institute for Regenerative Medicine (CIRM), will now help make the FDA-required safety studies for autologous stem cell therapy possible. Cherqui said support from the Sanford Stem Cell Clinical Center at UC San Diego Health was also crucial — they provide important resources for any basic researcher who needs expert help on how to move a potential therapy out of the lab and into the hospital. In addition, the CIRM-funded Alpha Stem Cell Clinic at UC San Diego Health is helping Cherqui remove barriers to the complex clinical trial of her stem cell therapy, which is expected to take place at UC San Diego in the near future.
Cherqui works closely with clinicians, too. Last year, she created the Cystinosis Stem Cell and Gene Therapy Consortium to bring together the various medical specialties that treat all of the organ systems affected by cystinosis.
The consortium includes gastroenterologist Dohil, pediatrician and clinical genetics researcher
Bruce Barshop, MD, PhD (who Nancy describes as the person who knows the most in the world about measuring cystine levels), nephrologists
Nadine Benador, MD,
Robert Mak, MD PhD, pediatric neurologist Doris Trauner, MD, endocrinologist Susan Phillips, MD, ophthalmologist
Eric Nudleman, MD, PhD, and; bone marrow transplant expert
Edward (Ted) Ball, MD, all at UC San Diego Health. Also involved are gene therapy expert Donald Kohn, MD, at UC Los Angeles, nephrologist Paul Grimm, MD, at Stanford University, and of course Nancy as patient advocate. (Schneider, who first developed cysteamine as a treatment for cystinosis, is now retired.)
“We’re so lucky we have all of these experts here at UC San Diego, especially now that we need to test all organ functions in cystinosis patients before and after autologous stem cell transplantation to know if this therapy works,” Cherqui said.
Today, at age 25, Natalie Stack is an independent adult beginning her career in social work — something she doesn’t think she could’ve accomplished before Procysbi, the 12-hour medication. Her mother, Nancy, said she has a huge heart and compassion for all types of people in need, likely because of all that she’s been through in her own life.
Recently, Natalie shared her story with guests at the Cystinosis Research Foundation’s annual fundraising event, where she said, “Cystinosis challenges me every day to be the best I can be, and though some days are just unbearable, every day I start anew and I think of all the love and happiness in my life… Although this disease can be exhausting, overwhelming and downright depressing, we always have [this community] to lean on."
To learn more about the featured medical specialties, please visit:
Ophthalmology and Eye Care
Pediatric and Adolescent Medicine
Sanford Stem Cell Clinical Center