Our teams from the MPS Society and RDRP were delighted to attend WORLDSymposium 2026 in San Diego. Catch up on the highlights and presentation notes shared by Sophie Thomas, our Senior Head of Patient Services and Clinical Liaisons.
Dive into your areas of interest sorted by condition or theme below: MPS II, MPS III, MLD, LAL-D, Fabry and newborn screening.
WORLD was truly encouraging. We had many great and productive meetings. Things are moving ahead for our community.
MPS II
The maturation of evidence: what time teaches us about MPS II
This presentation explained how treatment for MPS II Hunter is more effective when started early in life. Children who begin enzyme replacement therapy soon after diagnosis tend to experience healthier growth, better mobility and slower disease progression overall.
Early treatment offers children the best chance at maintaining stable health over time.
The presentation also emphasised that treatment remains valuable even when started later. Adults who begin therapy after symptoms have already progressed can still see meaningful improvements, particularly in areas like breathing and stamina though typically to a lesser extent than those treated in childhood.
Peter Marks-Roscoe O Brady award: accelerating the global pace of progress for rare diseases
Gene therapy is advancing quickly and is beginning to change the lives of people with rare genetic diseases.
Early successes such as treatments using viral vectors and CAR‑T cells, have already helped patients live longer and healthier lives, some more than 10 years after treatment.
These therapies work by targeting the underlying genetic cause of a disease and may offer long‑lasting benefits. However, challenges remain. Current gene‑delivery methods can require high doses that may trigger inflammation and more research is needed to ensure long‑term safety.
Rare diseases also make research difficult because there are often few patients and limited information about how the disease naturally progresses. Costs, manufacturing complexity and differences in approval processes across countries can also limit access.
Experts are working on solutions, including shared platforms that could speed development, lower costs and help more patients benefit from gene therapies in the future.
Transforming patient care in MPS II
The presentation highlighted how care for Hunter syndrome is rapidly evolving through earlier diagnosis, better coordinated medical management and promising future therapies. Newborn screening is expanding across many U.S. states, allowing babies with MPS II to be identified before symptoms appear, giving them the best chance for improved outcomes. Clinical care now depends on a multidisciplinary team spanning heart, lung, neurological and genetic specialists to monitor the many ways the disease affects the body throughout life. Looking ahead, innovative treatments such as blood–brain‑barrier‑crossing enzyme therapies and emerging gene therapies offer hope for addressing the cognitive decline that current treatments cannot reach, marking a shift toward more comprehensive, whole‑body and brain‑targeted care.
Intravenous tivdenofusp alfa for MPS II
The phase 1–2 study of intravenous tivdenofusp alfa for MPS II shows promising early results, demonstrating that the therapy can normalize or significantly reduce key biological disease markers, including those related to CNS involvement, where current treatments typically fall short. Children in the study experienced high rates of biochemical improvement, including normalisation of major biomarkers and reductions in markers of nerve and brain stress, alongside encouraging signs of stabilised or improved hearing, behaviour and cognitive function. While infusion‑related reactions were common, their severity and frequency decreased over time and were considered manageable, aligning with expectations for enzyme‑based therapies.
Overall, tivdenofusp alfa appears to be a well‑tolerated and potentially transformative treatment
that may address both the somatic and neurological aspects of MPS II, supporting continued advancement toward late‑stage trials and future regulatory consideration.
RGX‑121 study: intracerebroventricular gene therapy for MPS II
The RGX‑121 study evaluates a one‑time gene therapy designed to address the neurological symptoms of MPS II by delivering the missing IDS enzyme directly into the brain, and early results from infants and young children show strong promise. The treatment produced substantial reductions in toxic heparan sulfate levels in cerebrospinal fluid, a key driver of neurological damage in Hunter syndrome, and these reductions were maintained over time.
Clinically, many children demonstrated continued skill gain or stabilisation
rather than the cognitive decline normally expected in untreated MPS II, with the greatest benefits seen in those treated earlier and with milder symptoms at baseline. Safety findings were generally favourable: side effects were mostly mild to moderate, no discontinuations were linked to the therapy, and a reported death was assessed as unrelated to RGX‑121. Overall, these results support RGX‑121 as a potentially transformative CNS‑directed treatment that may alter the progressive course of MPS II when delivered early in life.
Ex‑vivo lentiviral gene therapy for MPS II
This presentation described early experiences using an experimental ex‑vivo lentiviral gene therapy for MPS II, where a patient’s own stem cells are collected, genetically corrected in the lab, and then returned to the body after chemotherapy to help them engraft. The goal is for these corrected cells to produce the missing enzyme long‑term. Five children have been treated so far, and although the treatment process is complex, early results are encouraging. Several children produced very high levels of the IDS enzyme. This is important, because high enzyme levels may help clear storage materials that build up in MPS II.
One child had a prolonged drop in blood cell counts, but this eventually resolved, and overall families reported that the children continued to do well after treatment. The investigators emphasised that the study is still ongoing and that funding challenges exist,
but the early outcomes suggest this approach may offer meaningful, long‑lasting benefits for children with MPS II.
MPS III
DNL‑126 for MPS IIIA (Denali Therapeutics)
Early clinical results for DNL‑126, an investigational enzyme therapy engineered to cross the blood–brain barrier,
show strong potential to address the neurological impact of MPS IIIA.
In the first 14 children treated, ranging from 2 to 18 years old, the therapy produced substantial reductions of heparan sulfate levels in cerebrospinal fluid, with some children reaching near‑normal levels, indicating effective delivery into the brain and direct engagement of the disease target. Improvements were also seen in urine biomarkers and liver size, suggesting broad systemic benefit, and these effects were maintained through 49 weeks of follow‑up.
Safety data were consistent with expectations for enzyme infusions: infusion‑related reactions were common but generally mild or moderate, decreased over time, and were manageable with standard supportive care, with no treatment‑related discontinuations or severe complications reported. Overall, these early findings support DNL‑126 as a promising CNS‑directed therapy that may alter the course of this devastating neurodegenerative condition, particularly with early intervention
36-month post-HSCT gene therapy for MPS IIIA
The highlighted MPS IIIA gene therapy study reports highly encouraging early results from an ex‑vivo lentiviral approach in which a child’s own stem cells are genetically corrected to produce the missing SGSH enzyme. Five children with severe MPS IIIA were treated, and all showed very high enzyme levels after infusion, along with reductions in heparan sulfate, the toxic substance that drives neurodegeneration in this disease. These reductions were seen in blood, urine and cerebrospinal fluid, indicating broad systemic and central‑nervous‑system engagement.
Early developmental outcomes showed skill gains or stability that deviate from the expected rapid decline of untreated MPS IIIA, while safety findings were consistent with expectations for stem‑cell‑based therapy. Some children experienced chemotherapy‑related complications, but no immune rejection occurred, and patients continued to do well following treatment. One child has maintained strong biochemical and clinical stability for more than two years,
underscoring the potential of this one‑time therapy to provide lasting benefit.
UX111 for MPS IIIA (Ultragenyx)
The presentation explained early clinical results for UX111, a treatment being developed for children with MPS IIIA. Across three clinical studies involving children at different stages of the disease, UX111 showed encouraging signs of benefit. Most children experienced a substantial and lasting reduction in heparan sulfate in the cerebrospinal fluid, meaning the treatment is reaching the brain and addressing the underlying cause of the disease.
One child who initially had an immune reaction improved after treatment of the reaction and is now responding better. Importantly, children treated with UX111 generally maintained or improved developmental skills compared to untreated children, who would typically show steady decline.
Families also reported consistent improvements in communication, motor skills, and daily living abilities.
Remarkably, eight children reached a developmental level that allowed them to complete more advanced cognitive testing, something never seen in the natural history of the disease. Even older children with more advanced disease were able to retain meaningful skills such as communication, walking and eating independently. UX111 was described as well tolerated, with any treatment‑related reactions manageable.
Overall, the findings suggest that UX111 has the potential to slow or stabilise the progression of MPS IIIA, providing hope for improving quality of life in both younger and older children.
TA‑ERT for MPS IIIB (Spruce Bio)
Long‑term data on tralesinidase alfa (TA‑ERT), a weekly enzyme replacement therapy delivered directly into the brain, showed sustained biological and clinical benefits for children with MPS IIIB. The treatment produced rapid and durable reductions of heparan sulfate and other disease‑related markers in cerebrospinal fluid, bringing them into the normal or near‑normal range for up to five years.
Children also showed improvements in body symptoms,
including normalisation of enlarged liver and spleen sizes, and stabilisation of brain volume, which typically declines in untreated MPS IIIB. Importantly, TA‑ERT was associated with preservation or continued gain of cognitive, communication and motor skills, representing a clear deviation from the predictable decline seen in natural history studies.
The therapy demonstrated a manageable safety profile, with device or infusion‑related issues but no unexpected serious events. Together, these findings suggest TA‑ERT may offer meaningful, long‑term slowing of neurodegeneration when started early in life.
LAL-D
Treatment of rapidly progressive LAL‑D with sebelipase alfa before transplant
Babies with rapidly progressive LAL‑D become very sick early in life and historically their only chance of survival was a high‑risk stem cell or liver transplant, often with poor outcomes. This presentation showed that treating these infants first with sebelipase alfa, a medication that replaces the missing enzyme, can stabilise their symptoms, improve growth and liver function and help them better tolerate a later stem cell transplant when needed. Some babies were able to come off the medication after a successful transplant, while others continued depending on their individual situation, and although most experienced at least one side effect, these reactions were generally manageable.
Overall, sebelipase alfa was found to be a safe and effective way to support these very fragile infants before transplant and may offer a valuable bridge to better long‑term health.
MLD
Norway MLD newborn screening study
Norway’s newborn screening team developed a highly accurate test for metachromatic leukodystrophy (MLD) that can be added directly to the standard newborn blood‑spot panel. In evaluations it clearly distinguished affected children from healthy controls and in real‑world screening of about 70,000 babies, including 56,000 in the prospective program,
it produced zero false positives, demonstrating exceptional reliability.
The program also proved capable of rapid clinical action: in a recent true positive case, the baby was flagged by day six, the family was contacted the next day, follow‑up testing began immediately and early treatment was initiated once the infant reached safe weight for therapy.
Overall, the study shows that MLD newborn screening is practical, accurate and ready for routine use offering families the chance for diagnosis and intervention before symptoms appear.
Fabry
ST‑920 (STAAR) gene therapy
The ST‑920 phase 1/2 STAAR study evaluated a one‑time gene therapy designed to enable patients with Fabry disease to produce their own enzyme, potentially replacing the need for lifelong infusions.
The therapy was generally well‑tolerated, with only mild, short‑term side effects reported and no serious treatment‑related complications.
After dosing, all patients achieved high, often above‑normal, levels of enzyme activity and many were able to discontinue standard enzyme‑replacement therapy, maintaining stability through long‑term follow‑up. Kidney function, a major concern in Fabry disease, showed stabilisation or improvement over 52 to 104 weeks, and patients demonstrated gains in symptoms, quality‑of‑life scores and cardiac biomarkers.
Immune responses remained manageable, with most patients not developing problematic antibodies. Overall, the results suggest that ST‑920 may offer a safe, durable, and effective one‑time treatment and the sponsor plans to move forward with regulatory submission based on these promising outcomes.
Comparison of outcomes of the FACTS lentivirus gene therapy in Fabry
The FACTS lentiviral gene therapy study for Fabry disease demonstrated that a single treatment using a patient’s own stem cells genetically modified to produce the missing enzyme resulted in stable, long‑lasting enzyme activity, reduced disease‑related substrate levels and the ability for patients to discontinue standard enzyme‑replacement therapy.
Over five years of follow‑up, patients showed stabilised or improved kidney function with declining kidney performance before treatment slowing dramatically or flattening afterward and urine protein levels improving following an early rise.
When compared with matched patients from a large external registry, the gene‑therapy group showed better kidney outcomes and similar or lower rates of serious clinical events, supporting the therapy’s potential to provide durable benefit.
These findings suggest that lentiviral gene therapy may offer a meaningful, long‑term alternative to lifelong infusions and support moving forward with expanded clinical evaluation.
Newborn screening
Michael Gelb’s presentation on newborn screening
Michael Gelb’s presentation highlights how cutting‑edge protein‑design technologies, similar to the AI systems used to generate images, can now be leveraged to
revolutionise newborn screening by creating highly precise, custom‑built biochemical tools.
These engineered proteins can detect disease markers with far greater accuracy, allowing screening programs to identify many more rare conditions long before symptoms appear.
Gelb emphasizes that while whole‑genome sequencing for all newborns remains years away, these new biochemical methods are available now and can dramatically expand screening capabilities, reduce false positives and help ensure that treatable diseases are caught early.
His central message is clear:
we should not wait for future technologies when powerful tools already exist that can save lives today.
Global access to newborn screening: a call to action
The discussion emphasised that newborn screening should be globally accessible, because
early diagnosis can save lives,
but many countries still face political, financial and regulatory barriers that prevent them from adopting proven screening tests.
Speakers described how international collaboration, especially through patient‑led groups like the MLD Alliance, has been essential for advancing screening efforts across borders, with experts sharing data openly to help other countries move faster.
They stressed that governments often delay screening because they aim for perfection, even when reliable and effective tests already exist,
causing babies to miss out on life‑saving early detection.
The panel argued that newborn screening must evolve:
it should be less rigid, more transparent, driven by real‑world data and supported by strong storytelling from patient communities.
They also highlighted that genomic and biochemical testing should work together and all stakeholders, families, clinicians, scientists and policymakers must unite in a common voice to ensure that every child, no matter where they are born, has access to timely, life‑saving screening.
These summaries were created from notes I took during conference presentations. While I have done my best to capture the information accurately, some details may have been interpreted differently from what the speakers intended or may contain unintentional inaccuracies. These summaries should not be considered complete or fully comprehensive and they do not replace any information or advice you have been given by your doctor or health professionals. If you have questions about any of the information, please speak with your doctor or specialist centre.
Sophie Thomas, 09/02/2026
