From Wish to Reality — The Gene Therapy Initiative at UC San Diego

Story by:

• Miles Martin- [email protected]

Topics covered:

• Gene therapy
• Stem cells
• Rare diseases
• Cystinosis
• Alzheimer's

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In 2003, while out to lunch with her mother on the eve of her twelfth birthday, Natalie Stack Morgan wrote a wish on a restaurant napkin: "to have my disease go away forever."

That disease was cystinosis, a rare genetic disorder that causes the amino acid cystine to accumulate in the body and damage cells. Though cystinosis is rare - affecting just 500 people in the U.S. and 2,500 worldwide - its impact is profound. Over time, the accumulated cystine slowly destroys virtually all of the body's organs, including the kidneys, eyes, liver, pancreas and even the brain. With treatment, the average life expectancy of somebody with cystinosis is approximately 28 years. Without treatment, most don't live past childhood.

Today, after receiving a gene therapy developed at the University of California San Diego, Natalie is thriving at 34 years old. She's built a career as a social worker, is happily married and recently became a mother - milestones that are often out of reach for people with cystinosis.

A call to action

When Natalie made her fateful wish, the Stack family had already been part of the UC San Diego community for a decade through Natalie's doctors at UC San Diego Health, including Jerry Schneider, M.D., one of the world's foremost experts on cystinosis. In the 1970s, Schneider played a key role in developing and testing the first treatment for cystinosis - a drug called cysteamine, which helps manage symptoms but isn't a cure. Cysteamine is a life-saving treatment, but it has its drawbacks - it tastes terrible, has unpleasant side effects, and must be taken every six hours, without fail, for life.

"We would wake Natalie up at 11 p.m. and 5 a.m. every single night," recalled Stack. "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. There are no days off with cystinosis."

For Nancy and Jeff, Natalie's wish was a call to action. Shortly after that fateful lunch, they started the Cystinosis Research Foundation, which has since raised more than $73 million for cystinosis and funded hundreds of studies worldwide The Foundation has also provided a beacon of hope for families living with cystinosis around the world.

"What I love about this community is that it feels like a family," said Nancy Stack. Families support each other through the ups and downs, and that sense of belonging and shared purpose keeps us motivated to fund research, volunteer for clinical trials, and keep hope alive, even when the disease is daunting."

In 2006, Jerry Schneider introduced the Stacks to Stephanie Cherqui, Ph.D., an ambitious young researcher from France who had helped discover the gene responsible for cystinosis.

"When we first sat down with Stephanie, we had no idea how her novel research ideas would impact us, but we were so impressed by her passion," Stack said. "Today, she is the rock star of our cystinosis community, and we are blown away by her determination to find a cure for our children."

With support from the Cystinosis Research Foundation, Cherqui's research has thrived since that initial meeting. Within a year, the Foundation awarded her a seed grant that enabled her to bring her laboratory to UC San Diego, where she could leverage cutting-edge stem-cell core facilities to discover a potential cure for cystinosis: a stem-cell based gene therapy that works by extracting the patient's own blood stem cells, correcting the mutation that causes cystinosis, then reinfusing the stem cells back into the patient, allowing the corrected gene to reach every organ in the body.

"This was the first bench-to-bedside gene therapy for rare disease to come entirely from UC San Diego," added Cherqui.

A bench-to-bedside ecosystem

While the cystinosis treatment is well on its way, having been recently licensed to Novartis Pharmaceuticals and advancing to a larger, phase II clinical trial, the GTI is also supporting projects at earlier stages in the hopes of empowering more bench-to-bedside research at UC San Diego.

To help make this happen, the GTI offers centralized resources for researchers to bridge the knowledge gap that often stalls therapeutic development between the lab and the clinic.

"We've organized symposiums, hands-onworkshops, targeted training programs, and promoted partnerships with industry to support investigators to develop their novel gene therapy approaches," added Cherqui.

One researcher who received a GTI seed grant is Brian P. Head, Ph.D., a professor of anesthesiology at UC San Diego School of Medicine and research career scientist with the Veteran's Administration. His gene therapy research takes a very different approach compared to Cherqui's. Instead of using stem cells as a vehicle to spread therapeutic genes throughout the body, Head's approach uses a viral vector - a modified virus that doesn't cause disease - to deliver a brain cell-specific neuroprotective gene straight into the brain and spinal cord, offering a new solution for neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis.

Many other therapeutic approaches to neurodegenerative diseases are based on monogenic targeting, which means correcting a specific type of brain damage caused by a single mutation rather than addressing the broader mechanisms driving the disease. For example, many Alzheimer's disease treatments only focus on removing accumulated proteins in the brain.

However, Head's approach is more fundamental. By delivering a neuroprotective gene directly into the brain, his approach can reprogram the behavior of brain cells, helping them to mitigate neurodegeneration and survive without relying solely on removing harmful proteins. In recent studies, this strategy has shown promise in restoring memory and cognitive abilities when delivered to post-symptomatic animal models of Alzheimer's disease, thus offering hope for a new way to halt or even reverse neurodegeneration.

Further, this approach recently received Investigational New Drug (IND) approval from the FDA, meaning it could enter human clinical trials by the end of this year - a major step in bringing the therapy out of the lab and into the clinic.

"The idea is to help brain cells survive and function even in the face of ongoing damage - whether it's Alzheimer's disease, ALS, or other neurodegenerative conditions caused by injury," said Head. "It's a fundamentally new strategy, and while translating it from animal models to human patients will take time and careful study, I'm optimistic that it could open the door to treatments for a wide range of brain disorders"

Breakthroughs begin with people

The story of gene therapy at UC San Diego is, at its heart, a story about people - patients, families, donors and scientists - working together to turn hope into cures.

Though they're excited about the progress that has been made, the Stack family is not letting up. They are passionate about seeing the impact of their support ripple out from the rarest diseases to more common conditions, such as Alzheimer's, cancer, glaucoma and immune disorders, all of which are being studied by GTI-supported researchers.

As Nancy Stack explains, "We discovered that ideas and discoveries in rare diseases can impact other conditions, and this was a surprise for us. It's exciting to see our small community making an enormous difference."

She also notes that grassroots organizations like the Cystinosis Research Foundation are critical now more than ever in the context of ongoing threats to federal research funding.