Hunter syndrome breakthrough: gene therapy shows early promise
The first patient treated with a stem cell gene therapy for Hunter syndrome is showing encouraging progress, nine months after receiving the treatment.
Oliver (Ollie) Chu was the first patient treated with a stem cell gene therapy for Hunter syndrome in an ongoing clinical study being delivered at Royal Manchester Children’s Hospital in collaboration with the Manchester Centre for Genomic Medicine at Saint Mary’s Hospital (both UK). Now, roughly 10 months after receiving the treatment, the Manchester researchers and Ollie’s parents are excited by the three year old’s progress.
Hunter syndrome
Hunter syndrome, also known as mucopolysaccharidosis type II, is an X-linked recessive disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. The IDS enzyme is necessary to break down complex sugar molecules and deficiency in it results in an accumulation of glycosaminoglycans in cells throughout the body, including the brain, causing symptoms like joint stiffness, hearing loss, breathing and heart problems, developmental delays and cognitive decline, resembling childhood dementia.
The standard therapeutic approach for Hunter syndrome currently consists of regular enzyme replacement therapy called Elaprase, where patients receive weekly intravenous administrations of IDS to help metabolize the excess glycosaminoglycans that build up in tissues, potentially reducing symptom severity and decelerating the disease’s advancement.
However, this therapeutic strategy has a significant limitation: the replacement enzyme cannot penetrate the blood-brain barrier. As a result, while the treatment may address systemic manifestations of the condition, it fails to impact the neurological aspects of Hunter syndrome, including cognitive decline and developmental delays that affect the central nervous system.
Crossing the blood-brain barrier
To address this critical limitation, the stem cell gene therapy that Oliver received produces an IDS enzyme with a proprietary ApoEII-tagged sequence added to it, which facilitates its transport across the blood-brain barrier.
The therapy involves collecting hematopoietic stem cells (HSCs) from the patient and using a lentiviral gene therapy vector to insert a functional copy of the IDS gene fused with a tandem repeat of the receptor binding domain of ApoEII. The modified HSCs are then infused back into the patient, where they engraft in the bone marrow and begin producing daughter blood cells that produce the ApoEII-tagged IDS enzyme. This tag enables the enzyme to cross the blood-brain barrier by binding to ApoE-dependent receptors, significantly improving enzyme delivery to the brain. Once in the brain, the enzyme can break down the glycosaminoglycans that accumulate and cause neurological damage, potentially preventing the devastating cognitive decline associated with Hunter syndrome.
Ollie’s progress
Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at the Manchester Centre for Genomic Medicine at Saint Mary’s Hospital and joint study lead, said: “Since having the gene therapy Ollie is no longer having weekly Elaprase infusions, but instead of seeing levels of the previously missing enzyme dropping we are seeing very high levels in his blood, and this is an extremely encouraging sign that the treatment is working.”
He added: “I have worked in researching treatments for children with rare genetic diseases for over twenty years and I have sadly seen many children lose their lives to these devastating conditions. This is a truly exciting development which could lead the way for treating similar genetic conditions and bring hope to other families.”
Ollie’s father, Ricky, spoke about Ollie’s progress: “Ollie is doing great since having the gene therapy. We have seen dramatic improvements, and he continues to grow physically and cognitively. Our hope for Ollie because of this treatment is that he will continue to make his own enzymes and live a normal life without infusions.”
Trial details
The clinical trial is being conducted at the University of Manchester, funded by LifeArc (London, UK), and is expected to run until April 2028. It is an interventional, non-randomized, single-arm, open-label Phase I/II trial designed to evaluate the safety of the gene therapy in patients. The primary objectives include assessing the engraftment of the gene therapy, as well as its short-term and long-term safety.