The WORLDSymposium™ was held as a hybrid meeting this year (7–11 February 2022) and brought together key opinion leaders from the field of lysosomal disorders and rare diseases. Here you can access summaries from the meeting, including reports with a specific focus on Gaucher disease.

Accredited provider: Postgraduate Institute for Medicine (PIM). Jointly provided by PIM and Saterdalen & Associates, LLC

Satellite symposium supported by an independent educational grant from Takeda Pharmaceuticals U.S.A., Inc.

Dr Uma Ramaswami (Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK) chaired this symposium, which aimed to address the opportunity for precision medicine in lysosomal storage diseases, including Gaucher disease. She introduced Professor Roberto Giugliani (Federal University of Rio Grande do Sul, Porto Alegre, Brazil), who presented the cellular mechanisms of lysosomal storage diseases, briefly introducing Gaucher disease and its pathology. He summarised that, in his clinical opinion, precision medicine may be a desirable approach to deal with complex and heterogeneous diseases such as Gaucher disease.

Dr Ozlem Goker-Alpan (Lysosomal and Rare Disorders Research and Treatment Center, Fairfax, VA, USA) then discussed the use of multiomics to aid the development of individualised treatment plans for patients, including the need for novel disease biomarkers. Precision (personalised) medicine involves assessment to select optimal therapies for a patient based on their genetic, molecular or cellular analysis.1 Dr Goker-Alpan explained the recent transition in rare disorders from what she termed “trial and error” treatments to personalised and bespoke medicine. She emphasised the importance of biomarkers as surrogate endpoints, and indicated that surrogates allow clinical results to be read earlier, while endpoints are reached later with longer follow-up to observe the clinical outcome.2 She explained the theory that ideally a surrogate acts as a substitute for the clinical outcome, as an intermediate step in the causal route from disease to clinical outcome. However, this is not always the case in clinical trials, especially where an intervention does not specifically target the disease pathology (non-specific therapies).2 In terms of biomarkers for Gaucher disease, glucosylsphingosine (lyso-Gb1) levels have been shown to correlate with GBA1 gene mutation severity in homozygous untreated patients.3 Dr Goker-Alpan used this as an example of how a biomarker used in the correct way with the right context can be a helpful surrogate. Finally, she summarised that the development of “omics” technologies may allow the advent of personalised bespoke medicine in Gaucher disease and other lysosomal storage diseases.

In the final part of the symposium, Dr Filippo Pinto E Vairo (Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA) discussed strategies to overcome the challenges of implementing precision medicine. He described how a limitation of multiomic technologies is how to integrate multiple datasets (genome, epigenome, transcriptome, proteome, metabolome and microbiome) in a unified way, to draw meaningful conclusions about how best to treat the patient.4 In Dr Vairo’s clinical opinion, the challenges of implementing precision medicine include: dealing with large and complex datasets; limited knowledge of how to interpret genomic data; lack of infrastructure to incorporate genomic data into clinical care; overcoming patient anxiety (fear of expensive tests, privacy concerns); and affordability. Strategies suggested to resolve these challenges may include5:

  • Training the workforce of the future in these new technologies
  • Integrating different data types through metabolic laboratories becoming functional genomics laboratories
  • Integrating bioinformaticians and data scientists in the patient care model
  • Increasing collaborations and data sharing
  • Leveraging patient-reported outcomes to get meaningful information from clinical trials.

Dr Vairo’s take-home message was that human involvement remains necessary for diagnostic and therapy decisions, no matter how automated the process becomes, and that he thinks the goal of precision medicine is to provide the right healthcare to the right population, at the right time and in the right place.

Satellite symposium supported by Sanofi Genzyme

Dr Virginia Kimonis (University of California Irvine, CA, USA) introduced the symposium, focussing on the role of glucosylceramide synthase (GCS) in lysosomal diseases. She began by reviewing the general pathology and symptoms of Fabry disease. Next, Professor James Shayman (University of Michigan, MI, USA) provided an overview of GCS and the importance of GCS inhibition in lysosomal diseases. He explained how most glycosphingolipids, which are plasma membrane components, are synthesised from ceramide via GCS.6 He described how GCS and galactosylceramide synthase, which catalyses similar reactions, have different biological functions and properties. For example, galactosylceramide synthase is distributed in the brain and kidney and localised to the endoplasmic reticulum while GCS is ubiquitously distributed and localised to the Golgi apparatus.6 Synthesis inhibition was proposed as a novel strategy for the treatment of lysosomal diseases, with the goal of finding a reversible inhibitor of GCS to prevent production of defective substrate.7 Professor Shayman described research that attempted to accomplish this, which eventually resulted in the discovery of eliglustat.8

The goals of the next generation of GCS inhibitors based on limitations of eliglustat were then discussed. In Professor Shayman’s opinion, these included to overcome extensive metabolism by cytochrome P450 2D6 (CYP2D6) and the low central nervous system penetrance. In the rest of his talk, Professor Shayman investigated novel enzymes and GCS inhibitors. In the final part of the symposium, Professor Johannes Aerts (Leiden University, Leiden, Netherlands) discussed sphingolipid metabolism in Fabry disease and Gaucher disease. He described the concept of substrate reduction therapy, introducing migalastat and eliglustat therapy.8,9 He went on to present data demonstrating reduced disease-related biomarkers, including glucosylceramide, during eight years of eliglustat therapy in adult patients with Gaucher disease Type 1.10

DISCLAIMER: The views expressed here are the views of the presenting physicians. The content presented in this report is not reviewed, approved, or endorsed by WORLDSymposiumTM, or any of its employees, agents, or contractors. No speakers or staff were interviewed directly or involved in the development of this report. Satellite Symposia are not part of the official WORLDSymposiumTM programme and WORLDSymposiumTM does not approve or endorse any commercial products or services discussed during the Satellite Symposia or offered for sale by any corporate supporter of the Satellite Symposia. Unofficial content. Official content is available only to registered attendees of WORLDSymposiumTM 2022. All trademarks are the property of their respective owners.

C-ANPROM/INT/GAUD/0132; C-ANPROM/INT/GAUD/0134; Date of preparation: February 2022