Manchester Calling: The Families and Scientists Refusing to Let Hunter Syndrome Go Unfunded

Ricky Chu, husband and father of two boys, was unprepared for the life-changing news he received in April 2024, when the elder of his two boys, Skyler, was on the cusp of his 5^th birthday. Skyler was diagnosed with a mucopolysaccharidosis (MPS)—a family of rare inherited metabolic diseases that can damage physical and mental development.

“I got a call from the metabolic doctor here at Children’s Hospital of Orange County (CHOC),” Chu told Inside Precision Medicine. “He said, ‘We did some enzyme testing, and your son Skyler has Hunter syndrome (MPS II). We want to talk to you in person about what this diagnosis means for the boys and your lives going forward.’”

Ricky didn’t give up after learning about Hunter syndrome, which is caused by genetic variants that disrupt the function of iduronate-2-sulfatase (IDS), an enzyme essential for breaking down large sugar molecules that can accumulate in tissues and organs.

Hunter syndrome has no cure. Instead, he and his wife, Jingru, resolved to face the daunting challenge of raising children with a rare genetic disease.

It started with insurance. The CHOC team recommended Hunter syndrome testing for Oliver (Ollie), Skyler’s one-year-old brother. Ricky’s health insurance company refused. Research led the Chus to two Taiwanese doctors specializing in MPS. “We made appointments,” said Chu, “and our doctors at CHOC told us, ‘If you’re going to Taiwan, you can probably do the testing there faster than for insurance to approve the testing here.’”

The Chu family traveled to Taiwan, where Ollie and Skyler, then one and four years old, respectively, and their parents underwent a host of tests—MRIs, X-rays, ultrasounds, enzyme testing, and more. Skyler was diagnosed in April 2024, and only a month later, in May, his brother Ollie also tested positive for Hunter syndrome.

Treatment—or lack thereof—was the second, more crushing obstacle. One of these few treatments is hematopoietic stem cell (HSC) transplants—in this case, from healthy donors to produce the missing IDH enzyme. Although there is no strict cutoff, the taiwanese clinicians, according to Chu, only did these transplants before irreversible neurological delays, which is about the age of one. There was a case in which a patient did a transplant at 14 months, but in that situation, the child had been diagnosed at six months, which provided sufficient lead time to find a match. Skyler was therefore ineligible and instead offered Elaprase, an enzyme replacement therapy (ERT) for IDS, which he started on his fifth birthday on May 29, 2024. Elaprase is one of the ten most expensive medications, with an annual cost ranging from $300,000 to over $800,000+ per year for weekly infusions, reducing mobility and organ problems but not mental decline.

After returning to Orange County, the Chus learned about Hunter syndrome clinical trials from CHOC doctors. There even had been one at CHOC, but the trial had been closed for a while.

Kristin McKay, president and executive director of Project Alive, directed Chu to clinicaltrials.org to find ongoing trials. Chu soon found a U.K. gene therapy trial for Hunter syndrome using modified autologous HSCs with lentiviral-based IDS gene therapy, only to get the wind of hope knocked out of him when he saw that the trial accepted children up to 20 months of age—Ollie was 21 months old.

The Chus had a series of phone calls with Evelyn Fisher, a genetic counselor from the MPS Society. “Evelyn said, ‘Our director [Matthew Ellinwood] is familiar with these research projects,’” Chu recalled, “‘But he’s on vacation in the middle of the ocean for two weeks. When he comes back, he’ll call you.’ I thought, there’s no way this guy’s going to call me back. Sure enough, the first day he gets back, he emails me.”

On the call with Ellinwood, the Chus referred to the U.K. trial for gene therapy. At first, the Chus were despondent, knowing that Ollie was a month too old for the trial. But Ellinwood had already contacted the trial lead, Simon Jones, and had good news—the U.K. team had raised the consent age to 22 months, so Ollie would qualify for the autologous therapy. In August 2024, Ollie was enrolled in the Hunter syndrome gene therapy trial, and Skyler, though too old for that trial, could enroll in another clinical research trial testing for an improved approach to ERT via infusions.

The following year, the Chus made nearly a dozen trips from Southern California to Manchester, U.K. Their next trip is on February 17, 2026, the treatment’s one-year anniversary. “They are both doing well and seeing lots of improvements,” Chu said in January 2026. “Both are mobile, verbal, and bilingual.”

A decade of quiet innovation

More than a decade before Skyler was born, a small group of clinicians and scientists began working on MPS disorders when few others were interested. One of those researchers, Brian Bigger, PhD, now professor of advanced therapeutics at the University of Edinburgh, was working on Sanfilippo syndrome (MPS IIIA) while he was a professor at the University of Manchester.

“That was back in 2015, when almost nobody was funded for gene therapy work, with very few gene therapy companies around at the time,” Bigger told Inside Precision Medicine. “We didn’t really think that this was ever going to get off the ground.”

Bigger said that the real turning point for the field of lentivirus-based autologous ex vivo gene therapy came in 2010 from the San Raffaele Telethon Institute for Gene Therapy in Milan (also known as “the Milan group”), showing meaningful benefit for MPS IIIA. That method harvests HSCs from the bone marrow, corrects them ex vivo with a lentiviral vector, and reinfuses them after the patient receives busulfan conditioning.

But Bigger, who was interested not only in Sanfilippo but the entire family of MPS, including Hunter syndrome, saw two glaring issues. The first deals with the timing of brain engraftment. This process, where gene-modified HSC-derived monocytes engraft in the bone marrow and later migrate into the brain to replace or supplement resident microglia, takes roughly six months, which is too slow for the rapid progression of Hunter syndrome.

This motivated Bigger’s team to create constructs for Sanfilippo and Hunter syndromes that use a myeloid-specific CD11b promoter to enhance brain delivery. This promoter targets the expression of enzymes in immune cells, which allows them to cross the blood–brain barrier (BBB) and enter the CNS. “I’ve had a lot of arguments over the years with people about using the CD11b promoter,” Bigger said. “A lot of people tell me that the CD11b promoter is too weak. You’re not going to get enough gene expression to be able to treat these diseases effectively, and we should be switching to the MND or a much stronger promoter. And I’m so glad we never did it.”

Though expression levels using were similar to those of a commonly used yeast promoter called PGK (named for the glycolytic enzyme phosphoglycerate kinase), CD11b shifted expression toward the brain, increasing relative enzyme activity at the pathology site. Importantly, some programs using the MNDU3 promoter, selected for its strong, ubiquitous activity, ended in serious safety issues. In seven of 67 children treated with Bluebird Bio’s gene therapy for early X-linked cerebral adrenoleukodystrophy—a neurological disorder that mostly affects young boys—blood cancers developed, possibly due to promoter choice.

There is an additional therapeutic mechanism to the ex vivo modified autologous HSC approach, which is that the engrafted HSCs and their progeny can not only engraft into the brain but also produce the replacement enzyme, which must cross the BBB. To address this second challenge in Hunter syndrome, Bigger’s group fused BBB-crossing peptides to IDS, specifically APOE. The resulting mouse data was clear—the tagged version of IDS outperformed the untagged version in brain distribution and cellular uptake.

That ultimately led the Sanfilippo program to become one of the co-founding programs licensed by Orchard Therapeutics from Bigger and colleagues at the University of Manchester in 2016 and from the Milan group two years later. In 2020, Cambridge, Massachusetts-based AVROBIO, a biotechnology company developing one-time gene therapies for rare diseases like Gaucher disease and Pompe disease, licensed the lentiviral-based HSC transplant for Hunter syndrome from Bigger and colleagues and the University of Manchester. But in July 2023, the company halted all development, including for Hunter, Gaucher, and Pompe diseases, to maximize shareholder value, not safety.

A trial on life-support

Confidence in gene therapy has been badly shaken by recent deaths in trials; however, those programs all used adeno-associated viruses (AAVs) and not lentiviruses. Furthermore, the FDA halted two of REGENXBIO’s AAV-based MPS gene therapy programs, including Hunter syndrome, on January 28, 2026, after a five-year-old Hurler syndrome participant developed a brain tumor. And for the one-time treatment using ex vivo modified HSCs that have been successful, the price tag has been astronomical. Lenmeldy, approved by the FDA in March 2024 for early-onset metachromatic leukodystrophy, is the most expensive drug on the market at around $4.25 million.

The clinical counterparts to Bigger in this story are Rob Wynn, MD, consultant hematologist at the Royal Manchester Children’s Hospital, who is a bone marrow transplanter and Simon Jones, MD, consultant in pediatric inherited metabolic disease at the Manchester Centre for Genomic Medicine at Saint Mary’s Hospital. Jones has been a proponent of the ex vivo gene-modified HSC approach, dissatisfied with Hunter syndrome bone marrow transplantation since early in his career due to enzyme dose and toxicity.

Jones said that on the clinical side, transplant-based gene therapy was dismissed for years. “We were told, ‘You’re faffing around with transplants, conditioning, and chemotherapy with poisonous drugs—you’ve got no chance. Why are you wasting your time?’” he recalled. “It was really tough. We had to fight on.”

When AVROBIO picked up the program, it looked like Jones finally had the shot he had been waiting for, only for it to slip away. Today, the Hunter syndrome gene therapy trial survives on what Jones bluntly calls “life support.” Sustained by charitable funding from LifeArc, a self-funded, not-for-profit medical research organization, the Manchester team is racing to generate enough data to persuade a partner to take a risk.

With the limited funding available, Jones has pushed the Hunter program forward. In addition to Bigger’s tagged IDS to promote earlier brain entry of the enzyme, Jones wanted to improve efficacy of the treatment by recruiting the youngest Hunter syndrome patients for the trial. Because there is an inherent delay for brain engraftment with the ex vivo modified autologous HSC approach, the trial began recruiting boys under 23 months, before developmental decline typically begins. On February 17, 2025, Ollie became the first child treated—and the results have been promising.

“At nine months, Ollie has developed beautifully and has developed lots more skills than he had nine months ago,” Jones said. “But he is not yet old enough to have fully diverged from normal developmental trajectory.” As of the last fornight week 2025, three boys had been treated.

Despite these early signals, funding remains precarious. “There’s been loads of interest, which we were really happy about. There was international press coverage, which was really encouraging,” Jones said. “But pharma companies don’t like doing five-year trials. They want a 12-month endpoint.”

Even if several children develop normally, Jones said that the Hunter program would still be faced with obstacles to keep the program alive. Regulatory approval may no longer be the hardest step; paying for and delivering gene therapies could be harder still. Jones has spent years working with regulators on cerebrospinal fluid biomarker-accelerated approval pathways to attract partners. But skepticism is now running high. “Gene therapy was oversold,” he said. “The pendulum has swung too far the other way. We shouldn’t throw the baby out with the bathwater.”

With only two years of funding, pressure is mounting. “We can probably complete our study on rescue charitable funding,” Jones said. “After that, we’re obliged to follow these children for at least 15 years. We will do that. But what we really hope is to find a company, an institution, or a large foundation willing to partner and move this forward.”

Small money matters

Andrew McFadyen is both a parent and a funder. Twenty years ago, McFadyen founded the Isaac Foundation to secure enzyme replacement therapy in Canada for his son with MPS VI. A response to an impossible diagnosis led to long-term MPS research funding, including Hunter syndrome.

In 20 years, the foundation has patiently raised and distributed countless $50–100,000 “small” grants. By pharmaceutical standards, these sums are negligible. However, McFadyen claims that rare diseases progress slowly, spreading risk over the years.

The Hunter syndrome story shows this approach’s promise and fragility. McFadyen heard Bigger present on MPS at a lysosomal disease conference years ago. Over coffee, McFadyen asked whether Bigger had considered applying the idea to Hunter syndrome, which he had not. When asked what it would cost to test the concept in the lab, Bigger estimated about $50,000. McFadyen funded it immediately.

The data were encouraging. As results accumulated, McFadyen believed that Bigger’s lentivirus-based HSC transplant approach, which was the foundation for the treatment Ollie received, was Hunter syndrome therapy’s future. Eventually, pharmaceutical interest followed. That was a moment validating McFayden’s efforts—the work had moved beyond philanthropy. For the first time, the Isaac Foundation was even offered residuals on its early investment. McFadyen had never expected money back, always viewing funding as money out the door. When the funds came, they were reinvested directly into Hunter syndrome research.

McFayden, Bigger, and Jones stayed focused, but companies acquired and dropped the program because reimbursement uncertainty, strict start–stop criteria, and the burden of evidence made the financial risk too high.

What followed makes Ollie’s story exceptional. Rather than letting the work die, Jones, Bigger and their colleagues refused to walk away. The team from Manchester dug in. Nonprofits partnered to fund the final stretch. The therapy moved forward, culminating in Ollie receiving a treatment that now allows him to walk through the world with real hope.

For McFadyen, the story echoes his own son’s journey. His son participated in a gene therapy trial in Italy that now looks increasingly like a cure for MPS VI. Even there, progress was not linear; dosing had to be doubled based on real-world results. At 14, his son expressed what many families feel but rarely say: he wanted to know if the therapy would work for someone like him, even if it was risky, so others could benefit.

These stories show why rare disease funding is so difficult. Parents raise money at neighborhood barbecues while companies calculate risks. It advances through regulatory fear and repeated setbacks. However, rare disease programs demonstrate what can be achieved with modest funding and conviction.

Ollie is walking because someone believed in an idea early and others kept it alive.

Jonathan D. Grinstein, PhD, North American editor for Inside Precision Medicine, investigates the most recent research and developments in a wide range of human healthcare topics and emerging trends, such as next-generation diagnostics, cell and gene therapy, and AI/ML for drug discovery. He is also the host of the Behind the Breakthroughs podcast, featuring people shaping the future of medicine. Jonathan earned his PhD in biomedical science from the University of California, San Diego, and a BA in neural science from New York University.