When a three-year-old from California flies to Manchester for a one-off experimental infusion, it is not just a family making a bet on science. It is a glimpse of a new kind of “passport medicine” in which access to gene therapy depends as much on geography, screening and logistics as on biology.
A rare disease that cannot wait
Hunter syndrome – or mucopolysaccharidosis type II (MPS II) – is the kind of diagnosis that collapses a family’s sense of time.
Children are usually born looking healthy. Somewhere between their second and fourth birthdays, parents start to see small things: frequent ear infections, a rounded belly, stiff joints, a coarseening of facial features, maybe delayed speech. Over the next decade, those “small things” often become a cascade: spinal and skeletal deformities, heart and lung disease, hearing loss, and, in the more common severe form, a progressive loss of cognitive skills that looks like childhood dementia.
The underlying problem is brutally simple. A mutation in the IDS gene means the body does not produce enough of an enzyme called iduronate-2-sulfatase. Without it, long sugar chains known as glycosaminoglycans (GAGs) accumulate inside cells and slowly poison tissues throughout the body and brain.
By any epidemiological measure, Hunter syndrome is rare, but not vanishingly so. Large cohort studies suggest an incidence of roughly one case for every 100,000 to 170,000 male births. Advocacy groups estimate that around 2,000 people are living with the disease worldwide, about 500 of them in the United States.
For families who fall into that tiny denominator, the natural history is unforgiving. In the neuronopathic (severe) form – the one this new gene therapy is designed to tackle – children often begin to lose basic skills such as speech and mobility between the ages of six and eight. Many die in their teens or early twenties from a combination of respiratory, cardiac and neurological complications.
Against that backdrop, shaving even a couple of years off the disease course is meaningful. Stopping it in early childhood would be transformative.
The limits of a half-million-dollar drip
Until now, the only licensed drug for Hunter syndrome has been Takeda’s Elaprase, a weekly intravenous enzyme replacement therapy (ERT) that drips synthetic iduronate-2-sulfatase into the bloodstream over roughly three hours.
Elaprase can shrink an enlarged liver and spleen, improve breathing and joint mobility, and reduce some of the GAG build-up in peripheral tissues. But the infused enzyme is large and does not cross the blood–brain barrier in meaningful amounts. Even on flawless weekly treatment, many children with the severe form continue to lose cognitive function.
The economics are as stark as the biology. In the UK, the list price is reported at around £375,000 per patient per year. In the US, analyses of idursulfase pricing and reimbursement put the annual drug cost in the half-million-dollar range, sometimes higher depending on weight-based dosing and contracts.
Do the rough maths. A boy started on ERT at the age of two, treated continuously into late adolescence, could easily generate drug bills in the high single-digit millions of dollars – before counting hospital time, ports, infusion centres, travel and parental time off work. Yet for the neuronopathic form of Hunter syndrome, that financial and emotional outlay still buys, at best, a partial reprieve.
For many families, the real burden is not the abstract cost curve. It’s the weekly rhythm: planning life around the next infusion slot, the next cannula, the next fever that might cancel the session.
Reprogramming the blood factory
The Manchester study that treated three-year-old Oliver Chu tries to change the equation by moving upstream – from treating the disease to rebuilding the child’s “blood factory” so it can make the enzyme on its own.
Instead of injecting enzyme into the bloodstream week after week, the clinical team at Royal Manchester Children’s Hospital collects Oliver’s own hematopoietic stem cells – the progenitors in bone marrow that continuously give rise to blood and immune cells. In a specialised laboratory at the Zayed Centre for Research into Rare Disease in Children at Great Ormond Street Hospital in London, those cells are exposed to a lentiviral vector carrying a working copy of the IDS gene tagged with a short ApoEII sequence.
The ApoEII “tag” is a clever engineering trick. In preclinical work, University of Manchester and UCL scientists showed that fusing IDS to this peptide allows the enzyme to hitchhike on ApoE-dependent receptors, cross the blood–brain barrier more efficiently and reach the central nervous system, while also circulating at high levels in blood. In mouse models of MPS II, the brain-targeted IDS.ApoEII construct not only cleared storage material but completely normalised brain pathology and behaviour, outperforming a version of the gene therapy that lacked the tag and a standard bone-marrow transplant.
The clinical trial – formally NCT05665166 – translates that idea into a first-in-human protocol. It is a Phase 1/2 study sponsored by the University of Manchester, aiming to enrol five boys aged between three and 22 months with neuronopathic genotypes. Their own CD34+ hematopoietic stem cells are mobilised and collected, transduced ex vivo with a lentiviral vector under a myeloid promoter to drive high enzyme production, then reinfused after myeloablative chemotherapy, typically using busulfan.
The goal is straightforward to state and hard to execute: engraft a population of engineered stem cells that will, for the rest of the child’s life, churn out supra-physiological levels of iduronate-2-sulfatase, including into the brain, without causing leukaemia or other long-term harm.
One boy, one experiment, and a long flight
Oliver’s case adds a human dimension to that protocol.
Diagnosed after his older brother Skyler was found to have Hunter syndrome, Oliver initially received the standard weekly Elaprase infusions at home in California. When testing showed that, at age three, he had minimal cognitive impairment, his parents decided to enrol him in the Manchester trial – even though that meant splitting the family, with Skyler participating in a separate study in the United States.
In February 2025, Oliver underwent stem-cell harvest in Manchester, received the gene-modified cells back after conditioning, and then spent weeks recovering from the transplant.
Nine months later, the early signals look encouraging. According to the research team, his previously undetectable enzyme activity has surged to very high levels in his blood, he no longer needs weekly Elaprase infusions, and his speech, agility and cognitive development have improved notably compared with his pre-treatment trajectory.
Clinicians are quick to stress that one child does not make a cure. There are only five places in the trial. The protocol requires at least two years of intensive follow-up, and the children will be monitored for 15 years for late effects such as insertional mutagenesis.
Still, for a family used to building life around a weekly infusion pump, the difference between “no enzyme at all” and “very high levels” is not abstract. It is the difference between constantly watching the clock and wondering whether a single, brutal month of chemotherapy might really have bought their child a normal school timetable.
A trial that recruits children – and their passports
If the Manchester protocol were simply a scientific story, it would already be noteworthy. But for Oliver and the other boys on the trial, it is also a story about geography.
The five participants are not local patients from northern England. They are boys flown in from the United States, Europe and Australia. None are from the UK, because by the time British children are diagnosed, they tend to have accumulated too much neurological damage to meet the inclusion criteria.
That diagnostic delay is not unique to Hunter syndrome. Globally, rare-disease patients can wait four to five years on average for an accurate diagnosis, and more than 95 per cent of the roughly 7,000 rare diseases still lack an approved therapy.
For Hunter syndrome, one solution is obvious on paper: screen newborns so that infants with the disease can be identified before symptoms appear. In August 2022, US federal advisers added MPS II to the Recommended Uniform Screening Panel (RUSP), signalling that every state should include it in heel-prick newborn screening programmes.
Reality is more patchy. A systematic evidence review found that, until recently, only Taiwan and two US states – Illinois and Missouri – had fully implemented newborn screening for MPS II, with pilot programmes in a handful of others. Analysts estimate that comprehensive screening across the US would identify around 59 affected babies a year at an additional laboratory cost of just a few dollars per infant.
Until such programmes are universal, however, eligibility for trials like the Manchester study will be biased towards families with the means, health-system literacy and luck to secure an early diagnosis and an intercontinental plane ticket.
In that sense, Oliver’s journey is emblematic of a broader trend in rare-disease research: what could be called passport medicine. A small number of centres – in Manchester and London, in Boston or Philadelphia, in Doha – accumulate enough expertise and infrastructure to run cutting-edge gene-therapy studies. Patients and families, rather than the therapies, are the ones that have to travel.
The ethical literature is only starting to catch up. Bioethicists have pointed out that sponsors increasingly offer travel support and accommodation to families relocating for rare-disease trials, but that even generous packages do not fully mitigate the social and economic disruption – siblings left behind, jobs put on hold, complex visa arrangements – nor do they solve the inequity for families who cannot travel at all.
Built on a decade of ex vivo gene therapy
Technically, what Manchester is doing is not magic. It is the latest iteration of a platform that ex vivo gene-therapy teams have honed over more than two decades.
In October 2025, researchers from Great Ormond Street Hospital (GOSH), UCL and UCLA published the largest long-term dataset yet for lentiviral ex vivo gene therapy, in children with the immune deficiency ADA-SCID. Among 62 patients treated between 2012 and 2019, all survived, 95 per cent were effectively cured, and responders were able to stop enzyme-replacement therapy and respond normally to childhood vaccines. The average follow-up was seven and a half years, with some children tracked for more than a decade. Serious complications such as leukaemia were notably absent.
Other neurometabolic disorders have followed. In Hurler syndrome (MPS I), a related lysosomal storage disease, ex vivo hematopoietic stem-cell gene therapy has delivered extensive metabolic correction in both peripheral tissues and the central nervous system in early clinical work, providing proof of concept that transplanted, gene-corrected cells can protect the brain.
For Hunter syndrome itself, University of Manchester and UCL teams have spent years optimising vectors and manufacturing processes, from early mouse studies with IDS.ApoEII constructs to GMP-grade stem-cell production protocols. The Manchester trial is the first time those elements – brain-targeted enzyme, autologous stem-cell transplant and rare-disease clinical know-how – have all been applied to MPS II in infants and toddlers.
Seen in this light, Oliver’s therapy is not a one-off wonder. It is a test of whether a platform that has worked remarkably well in immunology and some neurometabolic diseases can be extended to a new indication where the brain is the main battleground.
From lifetime bills to one brutal month
The trade-offs, however, are different from a weekly infusion.
Ex vivo hematopoietic stem-cell gene therapy is not a simple outpatient injection. It is closer to a bone-marrow transplant without a donor: central line insertion, myeloablative chemotherapy, infection risk, weeks in protective isolation. Even in expert hands, this is a tense and sometimes dangerous month for a young child and their family.
If the therapy works, that intense month may be followed by decades of freedom: no weekly Elaprase, fewer hospital visits, no port flushes, no infusion reactions. For payers, there is a parallel shift from an indefinite stream of half-million-dollar invoices to a single, very large upfront bill for a one-time procedure.
Across cell and gene therapy as a whole, regulators and analysts now count roughly three dozen approved products worldwide, including around 18 gene therapies that are not CAR-T cell infusions. List prices for one-off gene therapies for other rare paediatric conditions – such as spinal muscular atrophy or haemophilia – typically land between US$1.5 million and US$3 million.
Set against a lifetime of Elaprase at roughly US$500,000 a year, a curative therapy in that price band could, on paper, be cost-saving over the long run for public health systems and insurers, even before accounting for quality-of-life improvements. But that “on paper” hides hard questions: Who pays upfront? How do you reimburse a university-led treatment manufactured at an academic cell-therapy facility rather than by a listed biotech company? How do you handle families who cannot safely undergo high-dose chemotherapy?
Institutions such as GOSH and the charity LifeArc are experimenting with one answer: hospital-held licences for gene therapies that risk being commercially orphaned because the patient population is too small for industry to maintain a conventional product. If that model scales, the Manchester protocol could eventually move from “clinical trial” to “specialised service”, with costs negotiated more like transplant programmes than high-margin drugs.
Who gets on the plane?
For now, though, the case of Oliver and the other trial participants exposes how lumpy access to gene therapy remains.
On one hand, global infrastructure is improving. The Zayed Centre in London is now one of the world’s largest academic manufacturing units for gene and cell therapies, with multiple clean rooms turning out advanced therapies for trials across the UK. In Qatar, Sidra Medicine has launched a gene therapy centre targeting spinal muscular atrophy and Duchenne muscular dystrophy and explicitly courting international patients from across the Middle East and North Africa. Networks such as AGORA in Europe aim to pool regulatory experience and financing to broaden access to novel gene therapies that might otherwise stall after early trials.
On the other hand, global rare-disease epidemiology is sobering. More than 300 million people worldwide live with a rare disease. Around 80 per cent of these conditions are genetic, most begin in childhood, and roughly 95 per cent still have no approved treatment.
That makes Oliver’s path – rapid diagnosis, access to standard ERT, then enrolment in an overseas cutting-edge trial with long-term follow-up – atypical even by rare-disease standards. Families without passports, visas, flexible employers or English-language fluency are far less likely to find their way into similar studies, even if their children have the right genotype.
From a scientific perspective, this matters because trials need genetic and ethnic diversity if results are to generalise beyond a narrow subset of patients. From an ethical perspective, it matters because one child’s transformed future should not depend almost entirely on where their parents can afford to fly.
What this one child can, and cannot, tell us
It is tempting to see Oliver’s nine-month progress as a tipping point. After all, we have seen this pattern before: a string of harrowing stories of children tethered to infusion pumps, followed by a headline about a “one-shot cure” and then – a few years later – a licensed gene therapy for at least some patients with that condition.
The history of Hunter syndrome urges more caution.
Not so long ago, another futuristic approach – in vivo genome editing using zinc-finger nucleases delivered to the liver – was hailed as a landmark. Beginning in 2017, Sangamo Therapeutics ran the CHAMPIONS trial, infusing adults with an AAV vector designed to slice the IDS gene into the albumin locus of hepatocytes and generate a stable supply of enzyme. Early readouts confirmed that editing occurred in the liver, but enzyme levels in the blood did not rise to clearly therapeutic levels, and the approach has not yet translated into an approved product.
By contrast, the ex vivo platform underpinning the Manchester trial comes with a much stronger evidence base from other diseases, and the preclinical work specifically targeting the brain in MPS II is compelling. But even with that track record, scientists will want to see several years of follow-up data in more than one child before declaring victory:
- Are GAG levels in cerebrospinal fluid and brain imaging markers durably normalised?
- Do children maintain age-appropriate cognitive scores into school age?
- Does high-level, lifelong enzyme expression carry any unforeseen toxicities?
- How does the risk–benefit profile compare with emerging blood–brain-penetrant ERTs and AAV-based gene therapies such as Regenxbio’s RGX-121, which has reported large reductions in CSF biomarkers and allowed many patients to stop intravenous ERT?
Oliver’s story, in other words, is best read as a highly promising datapoint within a crowded pipeline. Biotechs Denali and JCR are advancing engineered ERTs that cross the blood–brain barrier, while multiple groups pursue AAV and ex vivo approaches; market analysts expect the Hunter-syndrome treatment market roughly to double between 2018 and 2032 as these programmes mature.
Turning exceptions into infrastructure
What, then, should policymakers, clinicians and investors take from a single Californian toddler thriving after a winter in Manchester?
Three themes stand out.
First, newborn screening is not a technical afterthought; it is the gateway. Without early, pre-symptomatic diagnosis, sophisticated ex vivo gene therapies will remain boutique interventions for a handful of children rather than a standard of care. That means not only adding MPS II to panels on paper, but also funding labs, developing algorithms to triage screen-positive infants, and counselling families about options in time to matter.
Second, manufacturing capacity is policy. Academic facilities such as the Zayed Centre in London are quietly becoming as important to rare-disease care as ICU beds or transplant theatres, because they determine how many patients can realistically receive bespoke gene therapies each year. Decisions about funding, licencing and cross-border referrals will shape whether protocols like Manchester’s remain one-off trials or scale to hundreds of children across Europe and beyond.
Third, passport medicine is a warning sign. It is understandable that early-stage trials concentrate expertise in a few global hubs. But if a decade from now access to curative therapies for MPS II or other paediatric genetic diseases still depends on a family’s ability to secure visas and family leave, then the system will have failed to keep pace with the science.
For Oliver and his parents, the calculus today is simpler. A disease that once meant a near-certainty of decline and early death now comes with at least the possibility of a different future – one in which a single, harrowing month in hospital replaces a childhood spent under an infusion pump.
The real test of the Manchester experiment will not be whether one boy from California can grow up without weekly Elaprase. It will be whether that opportunity can be extended to every child with Hunter syndrome, wherever they are born, without turning a rare genetic mutation into a test of their family’s ability to navigate global healthcare.
