WORLDSymposium™ Recap

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We hope you will enjoy this detailed recap of the 17th Annual WORLDSymposiumTM held virtually February 8-12, 2021. This year’s WORLDSymposiumTM was extraordinary indeed. It featured impressive presentations of results from a number of clinical trials including for MPS I, MPS II, MPS IIIA, MPS IIIB. Many of these trials were initiated recently, while others were longstanding enough to document clear changes in neuropathic disease. Among the abstracts was also one of the first really encouraging approaches to treating ML II. These results represent truly momentous findings and progress for some of our most vexing clinical challenges.

While perhaps not as incredible as the results discussed above, there were also some pretty exciting studies with impact on the MPS and ML diseases, among which were ways to improve or limit the complications of immune responses to ERT or gene therapy. As always there were some interesting lessons from pre-clinical model work as well some intriguing findings in basic cell biology as well as studies of other lysosomal storage diseases that may point the way to improved approaches to address MPS and ML disorders.

Clinical Trial and Clinical Updates

This was a truly exciting year to be at the WORLDSymposiumTM. There were a number of clinical and translational research updates all of which involved a very promising approach to treating both systemic and brain disease in the MPS disorders. Below are thematic recaps with links to overviews of listed study’s details, followed by a sorted list of the same study’s details.

Ex Vivo Lentiviral Gene Therapy, Hematopoietic Stem Cells and Transplantation.

AAV Intrathecal Gene Therapy

IV Administered AAV Gene Therapy Designed to Treat the CNS

Blood Brain Barrier (BBB) Transcytosis Engineered Enzyme

Intracerebroventricular (ICV) ERT

Direct Intraparenchymal Brain Vector Administration

Clinical Studies in Ultra Rare Diseases

Small Molecule Drug Studies and the Lessons of Other Lysosomal Storage Diseases

Overcoming The Immune Response for Improved ERT and Gene Therapy

Important Pre-Clinical and Translational Studies

New Approaches on the Horizon

The Value of Basic Science in Better Understanding Disease

Developing Better Clinical Tools

Concluding remarks:

Jenny and Terri are engaged, as are all advocates and researchers, in a network to improve lives, which is what happens every day in the lives of the Society’s members and supporters. Research is a vital part of that network, but equally, and perhaps more important are those networks that support us all in our everyday work to improve the lives and outcomes for our MPS and ML families and patients.

Sincerely,

Matthew Ellinwood

CSO of the National MPS Society

Studies by Syndrome

MPS I

MPS I (The San Raffaella Telethon Institute with collaborators and Orchard Therapeutics (OTL-203), NCT03488394)

Ex vivo hematopoietic stem cell gene therapy for mucopolysaccharidosis type I (Hurler syndrome). Bernhard Gentnerat the San Raffaele Telethon Institute for Gene Therapy, Milan, and clinical trial partners.

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MPS I (REGENXBIO, RGX-111, NCT03580083)

Intracisternal administration of AAV9 gene therapies to target the central nervous system. Bryan Pukenas at REGENXBIO clinical trial partners.

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MPS I Clinical Trial samples evaluated as biomarkers for neurocognition (NCT00638547).

Biochemical predictors of neurocognitive outcomes in Hurler syndrome. Troy Lund and colleagues at Univ of Minn and clinical partners.

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MPS II

MPS II (GC Pharma, Japanese intracerebroventricular Hunterase® clinical trail)

Prevention of cognitive decline in patients with neuronopathic mucopolysaccharidosis type II treated by intracerebroventricular enzyme replacement therapy: 100-week results of an open-label phase 1/2 study. Torayuki Okuyamaat the National Center for Child Health and Development (Tokyo), and clinical trial partners.

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MPS II (REGENXBIO, RGX-121, NCT03566043)

RGX-121 gene therapy for severe mucopolysaccharidosis type II (MPS II): Interim results of an ongoing first in human trial. Marie-Laure Nevoret at REGENXBIO, and clinical trial partners.

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MPS II (REGENXBIO, RGX-121, NCT03566043)

Intracisternal administration of AAV9 gene therapies to target the central nervous system. Bryan Pukenas at REGENXBIO clinical trial partners.

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MPS II (Denali Therapeutics, DNL310, NCT04251026)

Intravenous ETV:IDS (DNL310) significantly reduces cerebrospinal fluid heparan sulfate in an open label Ph1/2 study in MPS II patients. Anna I. Bakardjiev at Denali Therapeutics, and clinical trial partners.

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MPS III

MPS IIIA (The University of Manchester, with collaborators and Orchard Therapeutics (OTL-201), NCT04201405)

Ex-vivo autologous stem cell gene therapy clinical trial for mucopolysaccharidosis type IIIA: Update on phase I/II clinical trial.Jane L. Kinsella (young investigator awardee) and colleagues at the Royal Manchester Children’s Hospital and clinical trial

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MPS IIIA (Abeona Therapeutics, ABO-102, NCT02716246 and NCT04360265 (long term follow up))

Updated results of Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102 gene therapy for Sanfilippo syndrome type A (MPS IIIA). Kevin M. Flanigan and clinical trial partners and colleagues at Abeona Therapeutics

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MPS IIIA (LYSOGENE, LYS-SAF302, NCT03612869)

CNS-specific reductions of heparan sulfate and secondary storage biomarkers in Sanfilippo syndrome type A patients treated with the investigational gene therapy LYS-SAF302. Michaël Hocquemiller and clinical trial partners, and colleagues at LYSOGENE

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MPS IIIB (Abeona Therapeutics, ABO-101, NCT03315182)

Updated results of Transpher B, a multicenter, single-dose, phase 1/2 clinical trial of ABO-101 gene therapy for Sanfilippo syndrome type B (MPS IIIB). Maria J. de Castro and clinical trial partners, and colleagues at Abeona Therapeutics.

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MPS IIIB (Allievex, AX 250, NCT02754076 and extension study NCT03784287)

Tralesinidase alfa (AX 250) enzyme replacement therapy for Sanfilippo syndrome type B. Nicole Muschol and clinical trial partners, and colleagues at Allievex.

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MPS VII

MPS VII (Ultragenyx Pharmaceutical Inc., (Mepsevii/vestronidase alfa))

Significant unmet need in infants with mucopolysaccharidosis type VII and non-immune hydrops fetalis: A summary of cases. Deborah Marsden, and colleagues at Ultragenyx Pharmaceutical Inc.

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Pre-clinical and disease pathobiology updates

ML II

ML II gene therapy approach evaluated in normal mice (M6P Therapuetics)

Mucolipidosis type II AAV9 gene therapy pilot study: In vivo safety of over-expressing modified GlcNAc-1-phosphotransferase (S1S3) in wild-type mice

Robert R. Gotschall and colleagues at M6P Therapeutics.

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MPS I

MPS I mouse brain imaging

Functional connectivity alterations in MPS I mouse brain at the laminar level revealed by resting-state fMRI. Wie Zhu (young investigator awardee) and colleagues at the Univ. of MN.

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MPS I mice transplanted with neural stem cells

iPSC-derived human neural stem cells engraft in the brains of immunocompromised MPS I mice. Shih-hsin Kan and colleagues at the Children’s Hospital of Orange County.

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MPS I mice treated with a gene editing technology

Immunogenicity, genotoxicity, and efficacy of PS gene editing in treating MPS I mice. Li Ou and colleagues at the Univ. of MN.

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MPS I mice treated with AAV9 gene therapy via IV, intracisternal, and combined delivery

Comparative systemic and neurologic effectiveness of intravenous and intrathecal AAV9 delivered individually or combined in a murine model of mucopolysaccharidosis type I. Lalitha Belur and colleagues at the Univ of MN and REGENXBIO.

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MPS I mice and signs of neurodegeneration and neuroinflammation

Murine models of lysosomal diseases exhibit differences in brain protein aggregation and neuroinflammation. Jennifer Clarke Matthews and colleagues at Sanofi.

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MPS II

MPS II ex vivo lentiviral gene therapy and HSCT in MPS II mice (Bluebird Bio)

Ex vivo lentiviral transduction of hematopoietic stem cells in mucopolysaccharidosis type II (MPS II) mice achieves high levels of systemic iduronate-2-sulfatase (IDS) enzyme activity and normalization of glycosaminoglycans (GAGs). Miles C. Smith (young investigator awardee) and colleagues at the Univ of Minn and bluebird bio, Inc.

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MPS II therapy with implantation of encapsulated cells (Sigilon Therapeutics, SIG-018)

SIG-018: Novel encapsulated non-viral cell-based therapy for MPS II. Drew Tietz and colleagues at Sigilon Therapeutics.

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Studies on Blood Brain Barrier crossing IV enzymes in MPS II mice

Molecular architecture determines brain delivery of transferrin receptor targeted iduronate 2 sulfatase in a mouse model of mucopolysaccharidosis type II. Cathal S. Mahon and colleagues at Denali Therapeutics, Inc.

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MPS II mice treated with a blood brain barrier crossing Enzyme Transport Vehicle:IDS (ETV:IDS)

Iduronate-2-sulfatase transport vehicle rescues neurobehavioral and skeletal phenotypes in a mouse model of mucopolysaccharidosis type II. Annie Arguello and research partners and colleagues Denali Therapeutics, Inc. and research partners.

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MPS III

MPS IIIA mouse studies of the endocannabinoid system

Modulation of the endocannabinoid receptor CB2 as a novel treatment for the lysosomal diseases. Calogera M. Simonaro and colleagues at the Icahn School of Medicine at Mount Sinai, New York.

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MPS IIIB Study on PPS treatment of the CNS in a dog model

Treatment with pentosan polysulfate improves neuropathological measures in the canine model of MPS IIIB. Tyler Harm (young investigator awardee) and colleagues at ISU.

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Improving clinical efficacy with immune modulation approaches for ERT and gene therapy

Trial NCT01665326 in CRIM-negative Pompe disease patients involving ERT and immune tolerance

Transforming the clinical outcomes in CRIM-negative infantile Pompe disease identified via newborn screening: The benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Ankit K. Desai at Duke University and clinical partners.

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AAV treatment and immunosuppression studies in Pompe mice

Immunosuppression with bortezomib and anti-CD20 mAb is effective in reducing neutralizing antibodies to allow repeated AAV administration in mice. Su Jin Choi (young investigator awardee) and colleagues at Duke Univ.

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Neutralizing antibody ablation removes antibodies which interfere with AAV gene therapy

IdeS: An enabling technology to overcome the limitations of neutralizing antibodies to AAV gene therapy. Jeffrey M. Alexander and colleagues at Spark Therapeutics, Inc.

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Other Presentation with Implications for MPS and ML Including Basic Lysosomal Biology

COVID-19/SARS-CoV-2 and lysosomal storage disease patients

Impact of SARS-CoV-2 on patients with lysosomal diseases in a major NYC hospital system. Heather A. Lau at NYU School of Medicine

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Basic Cell Biology and Lysosomal Storage Disease

Novel regulatory function of GCN5L1 in lysosomal tubulation and biogenesis. Allen Seylani (young investigator awardee) and colleagues at the NIH

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ERT combined with a chaperone or substrate reduction drug therapy

Late Onset Pompe Trial

Top Line Results From the PROPEL Phase 3 Study Comparing AT-GAA (cipaglucosidase alfa/miglustat) versus alglucosidase alfa/placebo in Late Onset Pompe Disease. Benedikt Schoser at the Ludwig-Maximilians-Universität München, Munich, Germany.

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Gaucher disease type 3 Trial

Venglustat combined with imiglucerase positively affects neurological features and brain connectivity in adults with Gaucher disease type 3. Raphael Schiffmannand clinical partners, and colleagues at Sanofi Genzyme.

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Monitoring ex vivo gene therapy treated stem cells

Analysis of genetically engineered stem cell product and follow up of gene therapy patients through high-throughput single cell technologies. Cristina Baricordi and colleagues at Univ of Calgary and AVROBIO, Inc.

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Overcoming low numbers: Improved statistically approaches to rare disease trials with limited patients

A survey of statistical study design and analysis methods for rare disease development programs. Miganush Stepanians at PROMETRIKA, LLC.

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ML Research Collaborations

The Mucolipidosis Collaborative Research Network (MCRN). Jennifer J. Klein and MCRN member colleagues.

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The National MPS Society exists to cure, support and advocate for MPS and ML.

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