The WorldSymposiumTM sessions on Monday 8 February included presentations that summarised the effects of Gaucher disease mesenchymal stem cells on osteogenesis, osteoclastogenesis and adipogenesis; rare disease registries; and the role of heat shock proteins in lysosomal disease.

Basic science and satellite symposia

Dr Paula Rozenfeld (Universidad Nacional de La Plata, IIFP, CONICET, La Plata, Argentina) presented results from a study that evaluated the potential of mesenchymal stem cells (MSCs) from patients with Gaucher disease to differentiate towards osteoblast and adipocyte lineages and their role in osteoclastogenesis.1 The pathophysiology of bone mineral density problems in Gaucher disease is not completely understood, and there are two competing hypotheses to explain it: reduced bone formation (osteogenesis) or increased bone resorption (osteoclastogenesis). This study hypothesised that glucocerebrosidase deficiency in Gaucher disease MSCs inhibits osteogenesis and increases adipogenesis, and the inflammatory microenvironment increases osteoclastogenesis. This hypothesis was investigated using an in vitro model of MSCs in Gaucher disease, derived from induced pluripotent stem cells.1

It was found that Gaucher disease osteoblasts had lower bone matrix formation, shown by reduced mineralisation, collagen deposition and alkaline phosphatase (ALP) activity. There was also lower differentiation of these MSCs to osteoblasts, through decreased gene expression of alpha-1 type 1 collagen (COL1A1), ALP and RUNX family transcription factor 2 (RUNX2). Gaucher disease MSCs were also found to induce osteoclastogenesis, through the observation of increased osteoclasts and resorption area in the Gaucher disease model versus control. Increased osteoclastogenesis was mediated by interleukin 1 beta (IL-1β) and receptor activator of nuclear factor kappa-β ligand (RANKL). There was upregulation of inflammasome genes in Gaucher disease MSCs; lower sirtuin 1 (SIRT1) and higher NOD-like receptor family pyrin domain containing 3 (NLRP3) expression was observed. Dr Rozenfeld explained that this may link to the chronic inflammation observed in patients with Gaucher disease, as the active inflammasome induces caspase 1, which causes IL-1β production. Dr Rozenfeld concluded from these results that there is decreased bone matrix formation and osteogenesis, and increases in the proinflammatory profile, osteoclastogenesis and adipogenesis in Gaucher disease, which may likely contribute to the skeletal imbalance observed in patients with Gaucher disease.1

Satellite symposium supported by Sanofi Genzyme

Dr Pramod Mistry (National Gaucher Disease Treatment Center, Yale School of Medicine, New Haven, CT, USA) opened the symposium by emphasising that, in his opinion, prior to the initiation of the Gaucher, Pompe and Fabry disease registries, there was limited clinical understanding of these disorders. He indicated that these registries have contributed real-world data to help advance disease knowledge, thereby benefitting patients. Key discussions within the symposium highlighted the following:

  • The past – clinical care and knowledge before the introduction of the registries
  • The present – the benefits to the medical community, including real-world data and how they impact treatment, and monitoring guidelines and long-term patient outcomes
  • The future – pursuing unmet needs through collaboration between the registries.

Dr Mistry continued the discussion by outlining the inception of the International Collaborative Gaucher Group (ICGG) Gaucher Registry in 1991, which is now an international, multicentre registry that aims to characterise the phenotypes and manifestations of Gaucher disease.2 He also emphasised that, in his opinion, the learnings from the ICGG Gaucher Registry extend beyond this single registry and its patients and clinicians. In Dr Mistry’s opinion, the registries may have enabled clinicians to make value-based assessments of treatments. 

Next Dr Priya S Kishnani (Duke University Medical Center, Durham, NC, USA) emphasised that, in her opinion, the lessons learned from the ICGG Gaucher Registry are applicable to other rare disease registries. For example, she highlighted that until the Pompe Disease Registry Protocol was initiated in 2004,3 the extent of genotype variability was unknown. In Dr Kishnani’s opinion, regional variations in Pompe disease genotype are now better understood, which may help clinicians to understand the disease course and develop a treatment plan. She then highlighted that multiple publications have elucidated the disease variability among patients with Pompe disease as a result of the Pompe Disease Registry Protocol. For example, one registry publication supported findings from smaller natural history studies that described clinically distinct disease courses based on symptom manifestations when patients were aged >12 months versus ≤12 months.4 In addition, diagnostic advances leading to earlier diagnosis have arisen as a result of the Pompe Disease Registry Protocol.5 Consequently, these findings led to the inclusion of Pompe disease within the Recommended Uniform Screening Panel, as outlined by the Secretary of the Department of Health and Human Services in the United States as part of their state universal newborn screening programme.6 Dr Kishnani stated that the lessons learned from rare disease registries may enhance the global perspective of these diseases, particularly in terms of patient management and treatment. Her outlook for the future of disease registries included potential incorporation of patient-reported outcomes and direct patient involvement, which are features she suggested may often be overlooked by the research community.

Dr Christoph Wanner (University Hospital of Würzburg, Würzburg, Germany; Head of the Fabry Center of Interdisciplinary Therapy) concluded this symposium by describing the initiation and development of the Fabry Registry in 2001.7 He noted that the Fabry Registry aims to enhance the understanding of Fabry disease manifestations and treatment outcomes to help clinicians develop recommendations to monitor patients and optimise care.7 Dr Wanner stated that many peer-reviewed publications have arisen from the data collected through the Fabry Registry. In his opinion, many of these data have enabled the delineation between paediatric and adult patients with Fabry disease, as well as symptom presentation in males versus females. Elucidation of genotype–phenotype variances and treatment status8,9 has also potentially aided clinical care of patients with Fabry disease.

In Dr Wanner’s opinion, information from the Fabry Registry may lead to future evaluation of pre- versus post-intervention analysis, which may aid the prediction of patient and treatment outcomes, thus enhancing clinical care. In addition, Dr Wanner also highlighted that he feels there is a need to include patient-reported outcomes in order to advance treatments and disease outcomes.

Satellite symposium supported by Orphazyme

Dr Thomas K Jensen (Orphazyme, Copenhagen, Denmark) and Dr Nikolaj HT Petersen (Orphazyme) presented this satellite symposium. The presentation was introduced by Dr Jensen, who began by emphasising the importance of proteins in the human body, and their key function in cell signalling, facilitating biochemical processes and maintaining cell structure.10 He then described the process of proteostasis; under normal conditions, proteostasis ensures that proteins are produced and appropriately folded, and ensures that abnormal or damaged proteins are degraded.11 Dr Jensen noted that misfolding of proteins may occur as a result of an imbalance in cell homeostasis and may lead to loss of protein function.12 Next, Dr Petersen highlighted that, in some instances, lysosomal storage diseases can be a consequence of protein misfolding.13

Dr Jensen then discussed the role of the heat shock protein system, which is a central component of cellular protein quality control functions and proteostasis.14 Heat shock proteins can assist in protein re-folding, and can dissolve protein aggregates to correct misfolding or facilitate degradation of aggregates.14 Dr Peterson then discussed heat shock protein 70 (HSP70), which can help re-fold misfolded proteins.15 Under stressful conditions, heat shock factor 1 (HSF1) amplifies the transcription of the gene that encodes HSP70, and consequently amplifies the production of HSP70. The increased levels of HSP70 can then protect cellular proteins from misfolding errors.15 Dr Jensen concluded the symposium by stating that it is possible that HSP70 could be used as a basis for addressing diseases associated with protein misfolding.16

 

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 2021. All trademarks are the property of their respective owners.

C-ANPROM/INT/GAUD/0024; Date of preparation: February 2021