The annual international Lysosomal Storage Diseases conference, WORLDSymposium 2023, was held in Orlando, Florida in February. Our Head of Research, Dr Lisa Melton, and CEO, Kerren Hosking were delighted to be able to attend in person for the first time after two years of remote attendance.
Sanfilippo Children's Foundation CEO, Kerren Hosking (left) with Sanfilippo parents and advocates (left to right): Elise Drake (Cure Sanfilippo Foundation), Jill Wood (Phoenix Nest Inc.), Cara O'Neill (Cure Sanfilippo Foundation) and Raquel Marques (Associação Sanfilippo Portugal)
“The opportunity to deeply connect with our colleagues from other Sanfilippo and MPS patient organisations, industry representatives, clinicians and researchers from all around the world was invaluable,” said Kerren. “We had extensive conversations around collaborative initiatives and advocacy for Sanfilippo, and benefited greatly from discussions with researchers and advocates working on other conditions."
Oral presentations and posters covered basic, translational and clinical research. Below we provide a summary of some of the key updates on Sanfilippo syndrome, including the latest clinical trial results. It was also fantastic to see the recently published consensus clinical guidelines for Sanfilippo syndrome presented by our colleague Dr Cara O’Neill from Cure Sanfilippo Foundation USA, with great interest from the audience.
Basic and translational research
Professor Kim Hemsley from Flinders University, Adelaide, discusses her poster describing the effects of an anti-inflammatory molecule in Sanfilippo type A mice with conference delegates.
It was great to see Australian researchers presenting on the world stage. Professor Kim Hemsley, from Flinders University, presented results from her Sanfilippo Children’s Foundation-funded project showing that a molecule targeting a particular part of the inflammatory cascade in the brains of mice with Sanfilippo syndrome can modulate the activity of inflammatory glial cells and reduce damage to neuronal axons.
Professor Maria Fuller, from The University of Adelaide, discussed the techniques developed in her laboratory to accurately distinguish, in a single step, the different forms of mucopolysaccharidosis (MPS) from biological samples such as urine, blood and dried blood spots. Already in routine use for diagnosis, the method may also help in monitoring responses to treatments in the future.
Professor Alexey Pshezhetsky of the University of Montreal described the impact of Sanfilippo syndrome type C on myelin (the insulating sheath around nerve fibres) and Dr Frederik Ashby from the University of Florida presented methods to measure the effects of Sanfilippo type B on bones in mice which could be used to monitor therapies that target the bones.
A new method to deliver SGSH enzyme to the brains of Sanfilippo type A mice using neural stem cells developed from patient-derived induced Pluripotent Stem Cells (iPSCs) was described, and promising results of a new type of AAV gene therapy treatment for Sanfilippo type B currently being tested in mice and large animal models was presented.
Preclinical research updates
Denali Therapeutics presented their preclinical data on EVT:SGSH, an enzyme replacement therapy for Sanfilippo type A. In this therapy the enzyme is fused to a molecule that is part of the machinery that transports iron across the blood brain barrier, allowing the enzyme to be administered by intravenous infusion. The results in mice show that the enzyme is found in high levels in all areas of the brain and in all cell types including neurons and the glial support cells. Levels of heparan sulfate are rapidly reduced in both the brain and cerebrospinal fluid (CSF), as well as in peripheral organs such as the liver. Lysosomal storage and inflammation in the brain are all corrected.
Denali is currently planning for a phase I/II trial in Sanfilippo type A. The interim results of a clinical trial using the same enzyme delivery technology in MPSII (Hunter syndrome) were also presented at the conference with promising signs of safety and efficacy, including cognitive improvements.
JCR Pharmaceuticals have also developed an intravenous enzyme replacement therapy, known as JR441, for Sanfilippo type A utilising the iron transport machinery. The results in mice show that the enzyme is found in high levels in all brain areas and at higher levels than that seen with unmodified enzyme. Heparan sulfate levels were normalised in the brain, CSF and peripheral tissues and brain inflammation was greatly reduced. They also showed that the impaired electrical function of the retina seen in mice with Sanfilippo type A is prevented by treatment with JR441.
JCR Pharmaceuticals are currently planning for a phase I/II clinical trial in Sanfilippo type A.The interim results of a clinical trial of the same enzyme delivery technology for MPS I (Hurler syndrome) were also presented with promising results for correction of heparan sulfate levels in the brain and improvements in language and motor development, mood and sleep.
Professor Patricia Dickson of Washington University, working in collaboration with Phoenix Nest Inc has developed an enzyme replacement for Sanfilippo type D. They have conducted preliminary dosing studies with intracerebroventricular (i.c.v.) injections in mice followed by a repeated dosing study with i.c.v injections every 14 days for 23 weeks. Sustained reductions in brain and CSF heparan sulfate were seen, as was reduction in inflammation in the brain, and improvements in autophagy and lysosomal storage. This data lays the foundation for a future clinical trial, together with a natural history study of patients with Sanfilippo type D currently being sponsored by Phoenix Nest.
Dr Shivakumar Pattada from BioStrategies LC also presented results of a novel strategy to deliver SGSH to the brain in a mouse model of Sanfilippo type A by fusing the enzyme to a lectin molecule. The lectin component binds to sugar molecules on the surface of cells and blood vessels, allowing the enzyme to cross the blood brain barrier and enter cells more easily. Their results show that delivering the enzyme by direct intravenous injection or via an AAV gene therapy vector achieves reduction of heparan sulfate to normal levels in the brain and spinal cord.
Clinical trial updates
Autologous Stem Cell Gene Therapy for Sanfilippo type A
Dr Simon Jones from Manchester University presented an update on the Phase I/II clinical trial sponsored by Orchard Therapeutics in which bone marrow stem cells are collected from patients, treated with gene therapy in the laboratory and then reinfused into the patient where they engraft back into the body.
Five patients aged under two with severe Sanfilippo type A (as determined by their gene mutation or family history) have been treated. The results show that the treated cells engrafted successfully and high levels of enzyme activity are detected in the cerebrospinal fluid of the patients. Heparan sulfate levels in blood and urine were rapidly reduced to normal levels. CSF heparan sulfate is also reduced to normal levels but with a slight delay which appears to be related to the time it takes for the stem cells to populate the brain. The adverse events experienced by patients were those that are typically associated with bone marrow transplant.
The patients have now been followed for between 9 and 30 months following treatment and the majority are now aged over three years when the effects of the disease on cognition become apparent. Four of the five individuals are showing gains in cognitive skills in line with typical development with continued development of speech, continence and complex play. All patients need to be followed for 36 months post-treatment before any firm conclusions can be drawn.
Tralesinidase-alpha enzyme replacement therapy for Sanfilippo type B
Dr Eric Zanelli from Allievex presented results from phase I/II trial of the enzyme replacement therapy for Sanfilippo type B called AX250 (Tralesinidase Alfa), administered weekly into the CSF via a port implanted under the scalp. 22 Sanfilippo patients have been treated to date with 17 of these having been followed for two years or more. In all patients heparan sulfate levels in the CSF were rapidly and sustainably reduced to normal levels and liver volumes were also reduced. Eight of the 22 patients have shown a good response to the therapy with cognitive development stabilising or improving. Brain volume as measured by MRI was also stabilised in these patients in stark contrast to the significant loss in brain volume seen over time in untreated children with Sanfilippo type B. Of the three children who were treated under the age of 3 years, 2 have shown cognitive development in line with healthy children.
These are very encouraging results and the company is now discussing the next steps for the therapy with the USA Food & Drug Administration.
“It was incredibly inspiring and heartening to see the progress being made and the breadth of research and collaboration on Sanfilippo syndrome on show at the conference,” said Dr Melton. “The clinical trial results are particularly exciting to see. With more clinical trials getting off the ground and the level of collaboration between industry, researchers and patient organisations, it makes me hopeful that treatment for Sanfilippo is just over the horizon.”
Dr Cara O'Neill (Cure Sanfilippo Foundation) and Dr Lisa Melton (Sanfilippo Children's Foundation) with their poster describing the development of the Consensus Guidelines for Clinical Care of Sanfilippo syndrome.