Gene Therapy from UCLA may give children their voice

A UCLA surgeon is developing a one-time gene therapy treatment for creatine transporter deficiency, a rare genetic disorder that prevents the brain from accessing vital energy and leaves children unable to speak or develop normally. 

Dr. Gerald Lipshutz, a professor of surgery, molecular and medical pharmacology, and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, began researching the condition after attending a patient symposium in Utah in 2022, where parents shared accounts of living with the devastating disorder.

"It sounds corny, I know," said Lipshutz. "But when you meet these families, you either walk away sad, or you stay and try to help." He stayed.

Creatine transporter deficiency affects approximately one in 225,000 individuals worldwide and is caused by mutations in the SLC6A8 gene. This gene produces the protein responsible for transporting creatine across the blood-brain barrier and into brain cells. Without this transporter, creatine cannot reach the brain, depriving it of a critical energy source needed for normal function.

The condition manifests in severe symptoms, including limited or absent speech, seizures, intellectual disability, and behavioral challenges that impact daily life. Children with the disorder lag behind their peers in speech, motor skills, and cognitive abilities. The condition is not included in newborn screening panels, often resulting in delayed diagnosis as parents spend years searching for answers.

While most of the body's energy comes from glucose, organs with high-energy demands, such as the brain, heart, and muscles, require creatine as a critical secondary fuel source to function normally. The absence of this fuel source creates widespread developmental problems that worsen over time.

Lipshutz entered rare disease research after his experience as a surgical transplant fellow at UC San Francisco, where he encountered patients receiving liver transplants for single-enzyme deficiencies. "I remember thinking there has to be a better way," he said. "We're transplanting entire organs because of one abnormal enzyme."

His team's approach differs from other research groups studying the condition. While some laboratories attempted to deliver gene therapies directly into the brain's cerebrospinal fluid, Lipshutz targets the bloodstream using a modified viral vector designed to cross the blood-brain barrier and deliver a healthy copy of the SLC6A8 gene throughout the brain.

Preclinical studies in mouse models produced promising results. Animals treated with a single, moderate dose of the gene therapy showed restored creatine levels in the brain and improvements in behavioral activity. However, the research faces technological hurdles, particularly in developing a viral vector that can cross the blood-brain barrier in humans.

The research has received support from the California Institute for Regenerative Medicine. Only a handful of laboratories worldwide study creatine transporter deficiency, and none have brought therapy to clinical trials. Funding for rare disease therapies remains a persistent challenge for researchers working in the field.

Recent publicity has increased awareness of the condition through Jeffrey Randall Allen, who won the YouTube celebrity MrBeast competition show "Beast Games" on Amazon Prime Video and dedicated his victory to his son Lucas, who lives with creatine transporter deficiency. Allen serves as vice chair of the Association for Creatine Deficiencies, the organization that hosted the symposium where Lipshutz first encountered families affected by the disorder.

Lucas was diagnosed at age two after what Allen describes as a long and frustrating "diagnostic odyssey" filled with months of worrying about missed developmental milestones. When Allen and his wife, Jen, finally learned what was afflicting their son, they realized they had an answer but no solution.

"That's when we realized our life wasn't about us anymore," Allen said. "It was about helping him and kids like him. And that gave us perspective and gratitude."

Lucas, who turns 8 years old, requires assistance with everyday tasks and faces severe speech challenges that affect his ability to communicate basic needs. The family manages his condition through constant care while balancing the needs of his older brother, Jack.

Allen's advocacy efforts extend beyond his television appearance. This past March, he walked 365 miles across California carrying a backpack with the weight of his son, a symbolic tribute to the 365 days each year Lucas carries the burden of his condition.

"Since the show aired, I've heard from people all over the world — from Argentina to academic labs — who now know about CTD and want to help," Allen said. "The Beast effect is real."

Lipshutz emphasizes that substantial preclinical work remains to be done before human trials can begin. "We don't have access to that technology yet," he said. "But if it works, it could change everything."

The next phase involves translating the success of mouse models to humans and securing additional funding for continued development. "We're being cautious," Lipshutz added. "There are still critical steps ahead, but we're doing everything we can to get there."

"Our goal is bigger than Lucas," Allen said. "It's about the kids like Lucas, and those who haven't even been born yet. If they can get therapy at birth, we've essentially eradicated this condition."

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