WORLDSymposium 2024 updates

The annual international Lysosomal Storage Diseases conference, WORLDSymposium 2024, was held in San Diego, USA, 4-9 of February. Our Head of Research, Dr Lisa Melton, was delighted to attend in person and hear the latest updates in Sanfilippo research and clinical trials and meet with other patient organisations, researchers, clinicians and industry.

The Symposium, attended by over 2000 participants, was also a great forum to showcase the newly launched International Sanfilippo Syndrome Alliance with a booth in the conference expo. This attracted plenty of discussion, and we look forward to more collaboration in the future.

Oral presentations and posters at the conference covered basic, translational and clinical research. Below is a summary of some of the key updates on Sanfilippo syndrome and closely related MPS, including the latest clinical trial results.

Basic and translational research

Dr Oriana Mandolfo and Dr Helen Parker from Manchester University presented work that adds to the growing picture of a role of inflammation in the symptoms and progression of Sanfilippo. Dr Mandolfo showed that systemic infections (affecting the body), can lead to worsening of inflammation and cell loss in the brains of mice with Sanfilippo syndrome and contribute to memory loss. Dr Helen Parker showed that the meninges, the membranes surrounding the brain, are also affected in Sanfilippo. They are thickened and contain larger numbers of certain types of immune cells that can send signals into the brain that may also worsen cell damage.

Other researchers presented their work using neuronal models derived from patients' cells to investigate disease mechanisms and potential treatments. Their early results indicate that Sanfilippo may cause changes in the ways neurons grow, make connections and communicate with each other.

Preclinical research updates

Professor Kim Hemsley from Flinders University, Australia, presented her work looking at how different routes of gene therapy administration can target the eye in Sanfilippo syndrome. She showed in mice with Sanfilippo type A that gene therapy delivered via injection into the brain’s ventricles (fluid-filled spaces) can prevent the loss of cells across the full diameter of the retina, but did not treat inflammation in the retina. Intravenous (IV) delivery of the gene therapy could only prevent the loss of cells in the outer parts of the retina but was better able to reduce inflammation across the retina. The work suggests that multiple approaches may need to be considered in the future to tackle all of the impacts that Sanfilippo has on the body.

Dr Elena Banchi and colleagues from Paris have developed a new type of adeno associated virus (AAV) gene therapy for Sanfilippo type B. The experimental therapy was delivered to very young mice via IV injection and provided full correction of lysosomal storage and inflammation in the brain and spinal cord, and prevented memory loss. The gene therapy also achieved good levels of enzyme activity in the brains and blood of dogs with Sanfilippo and they will investigate whether the therapy can prevent symptoms and disease progression in the dogs.

Dr Rafael Badell-Grau from the University of San Diego presented work on a gene-modified stem cell therapy in Sanfilippo type C mice using a technique that the team is already testing in a clinical trial in people with Cystinosis. In mice with Sanfilippo type C, bone marrow-derived stem cells carrying a healthy copy of the HGSNAT gene were able to reduce lysosomal storage and inflammation in the brain, improve liver and spleen size, reduce damage in the retina and improve motor function. The team will conduct longer-duration experiments to test the effects of the cell-based gene therapy on behaviour and memory in the mice.

The challenge of the blood-brain-barrier

A special symposium was dedicated to the science of delivering treatments across the blood-brain-barrier into the brain and technologies that are being used to overcome this challenge. Different delivery routes and different packaging and carrier technologies to take genes or enzymes into the brain are showing encouraging results in a range of neurodegenerative lysosomal storage disorders, including in preclinical studies in animals and in clinical trials. This includes technologies developed by companies such as Denali Therapeutics, JCR Pharma, GC Pharma and others that have shown very good results in animal models of Sanfilippo syndrome type A. These same technologies are showing promising safety and early efficacy results in clinical trials for the neurological forms of MPS I (Hurler syndrome) and MPS II (Hunter syndrome). The neurological effects of these two conditions also result from the build-up of heparan sulfate in the brain, so it is an encouraging sign for the clinical trials that some of these companies are commencing in people with Sanfilippo.

Clinical trial updates

Ultragenyx’s UX111 Gene therapy for Sanfilippo type A

Dr Heather Lau from Ultragenyx presented further interim data for their trial of UX111 (formerly Abeona Therapeutics ABO-102), an AAV gene therapy delivered via a single IV infusion. Longer term follow-up data was presented and focused on patients in the ‘modified intention to treat’ group (mITT). These 17 patients were enrolled under 2 years of age or over 2 years with a developmental quotient of more than 60. Data indicates that heparan sulfate levels were reduced in the cerebrospinal fluid (CSF) within one month of treatment in all 17 mITT patients. As of August 2023, 16 of the 17 patients showed improvements or stability in cognitive measurements, compared to the ‘natural history’ seen in untreated children who would typically show declines in cognition within this time. There was a strong correlation between total reductions in CSF heparan sulfate levels over time and higher cognitive scores, with 15 of 17 patients having both a reduction in CSF heparan sulfate and an improvement in cognitive function.

Ultragenyx has indicated that they will continue with the long-term follow-up of the patients whilst also working towards a submission to the USA Food and Drug Administration (FDA) for marketing approval. Cure Sanfilippo Foundation and Ultragenyx will be hosting a webinar on 26 March at noon US EDT (27 March 3 am AEDT, and recorded) - you can register here.

Orchard Therapeutics-sponsored trial of stem cell gene therapy at Manchester University

Dr Simon Jones from Manchester University presented updated interim results from the trial sponsored by Orchard Therapeutics of the ex-vivo autologous stem cell gene therapy for Sanfilippo. In this trial, the patient's own bone marrow stem cells were extracted, treated with gene therapy in the lab and then re-infused into the patient. The five patients treated in the trial have now been followed for 3 years. All were treated before they turned 2 years of age and were known to have the severe rapidly progressing form of the disease based on their gene mutation or through having an older sibling with severe disease. All have shown sustained high levels of SGSH enzyme activity in both blood and CSF and heparan sulfate levels were reduced to normal levels in blood plasma and urine, with a slower, but complete normalisation of HS in CSF. Four of the five patients have continued to gain cognitive skills and speech within the ranges of typically developing children, and do not display the typical behavioural symptoms of Sanfilippo.

Representatives from Orchard Therapeutics indicated that they will wait for further long-term follow-up data before proceeding to the next phase of development for the therapy.

Newborn screening

Professor Michael Gelb, a global leader in the development of newborn bloodspot screening techniques for lysosomal storage disorders, and Professor Maria Fuller from Australia, an expert in the development of clinical diagnostic tests for metabolic diseases, have worked closely together to develop a highly accurate blood spot test for MPS disorders. The technique uses mass spectrometry to identify the specific chemical signature for each MPS disorder in just one test. By combining the technique with a first-step screen of enzyme activity, Professor Gelb noted the technique has eliminated the previous concerns that newborn screening for MPS disorders would generate too many false positives. This is a great step forward towards the safe introduction of newborn screening for Sanfilippo and similar conditions.