WORLDSymposium™ 2021

The first presentation of the Emerging Trends session was opened by Dr Andrew P Lieberman (Michigan Medicine, University of Michigan, Ann Arbor, MI, USA), who began by stating that lysosomal storage disorders may be associated with a continuum of disease severity. In his opinion, the concept of lysosomal storage disorders and lysosomal functioning has evolved. He highlighted that lysosomes have multiple roles within a cell, and accumulation of storage material associated with lysosomal storage disorders can affect autophagy, cell viability, exocytosis, lipid homeostasis, membrane repair and signalling cascades, which are linked to lysosomal functioning.¹ Dr Lieberman described four pathways critical to lysosomal functioning, as outlined by Marques and Saftig (J Cell Sci 2019)¹:

• mTORC1 kinase and TFEB-regulated processes: regulation of lysosome biogenesis, autophagy and exocytosis, and cell homeostasis
• Mobility: the positioning and movement of lysosomes is important for cell functioning
• Repair: lysosomes are susceptible to damage and autophagy
• Contact sites: lysosomes can establish contact sites with other organelles such as the endoplasmic reticulum, mitochondria and peroxisomes, which may aid transport of cholesterol between organelles.

Dr Lieberman ended his presentation by highlighting that lysosomal storage disorders are characterised by multi-organ pathology caused by variations in the genes encoding lysosomal enzymes and proteins.² Further research into lysosomes has shown that impaired lysosomal growth and catabolic processes have been implicated in age-related diseases, cancer and neurodegenerative disorders such as Parkinson’s disease.³

The content of Dr Marc C Patterson’s (Mayo Clinic, Rochester, MN, USA) presentation was based on his own clinical experience. He emphasised that the approach to diagnosis of lysosomal storage disorders is evolving. In Dr Patterson’s opinion, the ‘traditional’ route to diagnosis may include assessment of symptoms, history-taking, clinical examination and investigation, leading to a diagnosis and subsequent disease management. The ‘contemporary’ approach to diagnosis of lysosomal storage disorders may now also include newborn screening and DNA sequencing panels and/or whole-genome or -exome sequencing. Based on his experience, Dr Patterson highlighted some ‘red flags’ that could lead a clinician to suspect that a patient may have a lysosomal storage disorder, including: multi-systemic disease where specific organs or tissues are linked to specific substrate(s); characteristic signs or symptoms; evidence of progressive substrate storage; positive family history of a lysosomal storage disorder; or the patient being a member of an at-risk group.

Next, Dr Patterson noted that symptom localisation may help to further refine a diagnosis of a particular lysosomal storage disorder. For example, in his experience, a patient presenting with anaemia, bleeding or infections may be suggestive of involvement of the bone marrow, liver or spleen. Therefore, recognition of specific signs and symptoms related to disease patterns may aid diagnosis. He emphasised that, in his opinion, it is important for clinicians to stand back and look at the patient as a whole, as there is overlap of certain signs and symptoms between some lysosomal storage disorders. He noted that some symptoms may be highly indicative of one disease, whereas others may be more subtle. Dr Patterson also highlighted that, in his experience, lysosomal storage disorder diagnosis is the product of a patient’s phenotype (based on clinical and imaging data), biochemistry (assessment of enzyme and biomarker levels) and gene variants. Dr Patterson concluded his presentation by restating that the ‘traditional’ approach to diagnosis of lysosomal storage disorders is evolving through the use of newborn screening and gene sequencing, which, for him, is possibly the most important emerging trend in this field of research.

Firstly, Ms Amy Gaviglio (US Centers for Disease Control and Prevention, Atlanta, GA, USA) provided a brief history of population-based screening. In 1968, the Wilson-Jungner criteria for selecting suitable conditions for population-based screening were developed, which were subsequently updated in 2008.^4,5 Ms Gaviglio highlighted a few key points from these criteria, for example: there must be an accepted treatment; a suitable test or examination must be available; an accepted policy on whom to treat must be in place; and the costs of screening, diagnosis or treatment must be weighed against the possible expenditure of medical care.^4,5 Ms Gaviglio then described the Federal Recommended Uniform Screening Panel (RUSP). She explained that the panel represents a list of diseases, recommended by the Secretary of the Department of Health and Human Services in the United States, which individual states can include as part of their newborn screening programme. Diseases are selected by the RUSP if there is a potential net benefit of screening; if there is a public health readiness to screen for a disease; and if effective treatments are available. The purpose of the RUSP is to establish a standardised list of approved diseases for newborn screening in the United States.⁶ Ms Gaviglio emphasised that approved diseases for newborn screening in the United States vary from state to state, and, in her opinion, other variations may also exist between states. These variations may include how testing for a disease is performed, and whether screening for the disease is mandated or based on consent.

Ms Gaviglio highlighted that, from her perspective, the benefits of newborn screening may lead to early treatment initiation soon after birth, and may change the disease spectrum, particularly for patients with mild or late-onset phenotypes. She also noted that in using newborn screening, it is important that access to treatment is universal and that any patients identified through screening receive the appropriate follow-up and care. As a result, Ms Gaviglio noted that, in her opinion, newborn screening may have ethical, legal and societal considerations. At the end of her presentation, Ms Gaviglio left attendees with the following questions:

• Should routine screening for diseases be considered outside of the neonatal period?
• Should there be a panel of diseases for voluntary screening?

Ms Patroula Smpokou (Division of Rare Diseases and Medical Genetics, Office of New Drugs, US Food and Drug Administration, Silver Spring, MD, USA) gave a general overview of the regulatory context of product development specifically for lysosomal storage disoders. She stated that the general principles of drug development are to generate scientific evidence that the drug is both safe and effective for its intended use, and to inform appropriate drug labelling. The phases of drug development include pre-investigational new drug (IND), IND (Phases 1–3) and new drug application or biologics licence application.^7,8

She listed the characteristics of an adequate and well-controlled study, designed to distinguish the effect of a drug from other influences. Firstly, it is essential to have an appropriate control for valid comparisons. Both the experimental drug and the control group should be similar in terms of important baseline and on-treatment variables that could influence outcomes. Ideally, a concurrent control is preferred versus non-concurrent. Examples of concurrent controls include using a placebo, no treatment or the standard of care (SOC). Non-concurrent controls should only be used in special circumstances, such as where there is an objective outcome, where a large drug effect is expected or where the course of disease is highly predictable or uniform.⁹ Another important characteristic is to have appropriate assignment of patients to groups, such that the baseline characteristics are similar. Ms Smpokou explained that the most effective way to ensure this is through randomisation, as this ensures groups are balanced even in unknown variables, which is important in rare diseases where less is known. Randomisation should be done unless there is a strong scientific reason not to do so. It is ethical to randomise in most cases, but there may be some considerations, especially if children are enrolled in the trial, such as whether it is ethical to give a placebo when there is a SOC already.⁹

The final point made by Ms Smpokou was that there must be well-defined and reliable methods of assessing response to treatment. Response to treatment should comprise evidence of clinical benefit and favourable effects on how the individual patient feels, functions or survives – making patient input a very important aspect. Clinical benefit can be measured directly (clinical outcome assessments [COAs]) or indirectly (surrogate endpoints). COAs include patient input and perspectives that are relevant to the disease and applicable to trial design. Biomarker assessments offer an indirect approach and should be reserved for special cases.¹⁰

A summary of the specific challenges in rare diseases included heterogeneous clinical presentations; incomplete knowledge of natural history to inform trial design; reluctance of patients to enrol in randomised or placebo-controlled trials. Finally, the ethical considerations and regulatory requirements for paediatric patient enrolment in trials represent additional challenges. There must be additional safeguards in place for children in clinical investigations and evidence to support the prospect of direct clinical benefit.

Dr Cara O’Neill (Cure Sanfilippo Foundation, Columbia, SC, USA) started by describing the shared goal of the medical community: to help patients live better lives, and to lessen their suffering. She then stated that the focus of her presentation would be about how we define the concept of ‘better’ for patients. The suggestion is to start with an understanding of the impact of the disease on the people who have it and what they would value most, before setting up a measurement.¹¹ Furthermore, patients should be engaged from the start by identifying research priorities.¹² Otherwise, complaints of affected individuals may not be factored explicitly into drug-development plans. For example, reducing repetitive movements, known as ‘stimming’, in autism has been used as an endpoint in developing treatments. However, members of the patient community have noted that the focus for future drug-development plans should be on improving communication difficulties.¹³

Dr O’Neill presented results of a qualitative study on the parent experience and unmet treatment needs for Sanfilippo syndrome disease-related symptoms in children.¹⁴ She noted that for diseases with a degenerative element, severe impairment and no current treatment options, parents reported feeling abandoned by the medical community, who tell them to ‘go home and make memories’. She went on to explain that the study highlighted that important themes related to unmet treatment needs were those with a cognitive, behavioural and psychological impact (communication, relationship and social deficits, frustration, etc) and those with a physical health impact (pain and headaches, mobility, sleep problems, etc). Dr O’Neill went on to emphasise that any benefit after treatment can be meaningful to families, even just a few more minutes of enjoyment of an activity; and that parents’ assessments of risk versus benefit indicated that parents would partake in a high level of risk (e.g., intensive, invasive medical procedures) for even a modest improvement in their child’s well-being.¹⁴

Dr O’Neill described how measuring ‘better’ can be done with more flexible trial designs and individualised endpoints to measure the symptom or function that is prioritised by the patient and is reasonably achievable. Furthermore, she stated that within-patient change is important to measure in heterogeneous populations. In conclusion, Dr O’Neill emphasised the importance of working with the patient community to enrich research and create a better future for them.

Dr Chester B Whitley (University of Minnesota, Minneapolis, MN, USA) firstly stated that, from his perspective, the course of the COVID-19 pandemic is rapidly changing and evolving. He began by discussing the chronology of the COVID-19 virus and presenting the timeline of the pandemic, as published on the website of the World Health Organization.¹⁵ Dr Whitley also discussed the pathophysiology of the COVID-19 virus, the number of clinical trials initiated because of the pandemic, the development of vaccines and available treatments, and the emergence of COVID-19 variants. He highlighted one website that publishes the trajectory and evolution of COVID-19 variants in real-time and clinical resources to aid clinicians in the diagnosis and management of COVID-19.^16,17

The final presentation was given by Dr Heather Lau (New York University School of Medicine, New York, NY, USA), who first provided a brief history of the COVID-19 pandemic in the United States since January 2020. Based on data from the Centers for Disease Control and Prevention in the United States, Dr Lau highlighted the signs and symptoms of COVID-19 in children and adults,¹⁸ as well as the persistent symptoms that may be experienced following acute infection with COVID-19.¹⁹ She also discussed the development of vaccines for COVID-19 and treatments for the management of COVID-19 disease.

Dr Lau indicated that, from her perspective, patients with lysosomal storage disorders may be considered high risk for COVID-19 due to their baseline disease burden; however, this may vary depending upon the subtype of specific lysosomal storage disorders. In addition, patients with multi-systemic clinical manifestations may have a higher risk for COVID-19–related complications and made several recommendations for managing patients with lysosomal storage disorders during the COVID-19 pandemic.

Dr Lau concluded her presentation by emphasising that, in her opinion, clinicians should discuss the individual risk of COVID-19 with their patients with lysosomal storage disorders, and a risk-reduction strategy is recommended to be tailored to each patient, with management of the disease continuing throughout the pandemic.

Satellite symposium supported by Amicus Therapeutics Inc.
Dr Daniel Bichet (Hôpital du Sacré-Coeur, University of Montréal, QC, Canada) opened the symposium by providing an overview of Fabry disease and the current treatment options, which include oral chaperone therapy in the form of migalastat and enzyme replacement therapy.^20-22 Migalastat and its clinical trial data were the focus of this symposium.

Prior to organ damage, the effects of Fabry disease may be reversible; however, after this time point, damage could become irreversible.²³ Additionally, key considerations for optimising patient care were described, which included: providing a personalised approach; completing a comprehensive evaluation of disease involvement; early treatment initiation and use of adjunctive therapies, if indicated; thorough routine monitoring; and management by a multidisciplinary team experienced in Fabry disease.²⁴ Next, Dr Bichet highlighted two Phase 3 trials of migalastat: ATTRACT and FACETS.^25,26

Dr Roser Torra (Fundació Puigvert, Barcelona, Spain) and Dr Peter Nordbeck (University of Würzburg, Würzburg, Germany) then provided summaries of the renal and cardiac outcomes of two publications based on the ATTRACT and FACETS clinical trials. Dr Torra explained that results from the Phase 3 FACETS trial showed that migalastat significantly improved levels of interstitial capillary and glomerular cell globotriaosylceramide (Gb₃) in patients with amenable variants of the GLA gene when switching from placebo.²⁰ Additionally, proteinuria and estimated glomerular filtration rate levels were stabilised in patients with Fabry disease who received migalastat or enzyme replacement therapy during the 18-month and 30-month open-label extensions of the ATTRACT clinical trial.^27,28 Dr Nordbeck then highlighted that during the Phase 3 FACETS trial, migalastat significantly decreased left ventricular mass index in patients with Fabry disease, and in the 30-month open-label ATTRACT clinical trial for patients administered either migalastat or enzyme replacement therapy, mid-wall fractional shortening was unchanged from baseline.^20,28 Finally, Dr Bichet asked his co-presenters to provide their take-home messages from the symposium:

• Dr Torra emphasised that, in her opinion, the treatment goal for patients with Fabry disease is to prevent organ damage. However, if some organ damage is present, then the goal may be to slow disease progression. Furthermore, if an organ or organs are completely damaged then the recommended goal is to treat and protect the other organs.
• Dr Nordbeck agreed with Dr Torra, and believed that early treatment is important for patients with Fabry disease.

During the live Q&A session, the presenters answered questions from the audience based on their own clinical experience. Questions included differences in symptom manifestations of Fabry disease in young versus adult patients and the effect of the COVID-19 pandemic on patients. Dr Norbeck emphasised that, in his opinion, it is critical that clinicians discuss with their patients the importance of continuing to receive treatment during the pandemic.

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.²⁹ 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 data collected in 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 2004,³⁰ 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.³¹ In addition, diagnostic advances leading to earlier diagnosis have arisen as a result of the Pompe Disease Registry Protocol.³² Consequently, these findings led to the inclusion of Pompe disease within the Recommended Uniform Screening Panel, as outlined by the US Secretary of Health & Human Services 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 2001.³³ 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.³³ 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 status^34,35 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.³⁶ 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.³⁷ 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.³⁸ Next, Dr Petersen highlighted that, in some instances, lysosomal storage disorders can be a consequence of protein misfolding.³⁹

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.⁴⁰ Heat shock proteins can assist in protein re-folding, and can dissolve protein aggregates to correct misfolding or facilitate degradation of aggregates.⁴⁰ Dr Peterson then discussed heat shock protein 70 (HSP70), which can help re-fold misfolded proteins.⁴¹ 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.⁴¹ 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.⁴²

Satellite symposium supported by Sanofi Genzyme
Dr Susan Richards (Translational Medicine and Early Development, Sanofi Genzyme, Boston, MA, USA), who discussed the fundamentals of immunogenicity, delivered the first presentation of this symposium. She highlighted that the generation of an immune response to therapeutic proteins can cause the development of anti-drug antibodies, which may affect the efficacy and safety of some treatments.⁴³ Dr Richards noted that both the Food and Drug Administration and the European Medicines Agency use a tiered approach strategy to test for immunogenicity and anti-drug antibodies.^44,45 In some instances, anti-drug antibodies may correlate with a patient’s clinical response to treatment. For example, anti-drug antibodies may affect the pharmacodynamic and pharmacokinetic profile and exposure of a therapeutic protein, or its efficacy and safety.^44,45 In line with the guidance developed by the European Medicines Agency, Dr Richards noted that the age and genetics of a patient and/or disease-related factors may also influence immunogenicity.⁴⁵ The results of one publication by Lenders et al. (J Am Soc Nephrol 2018) in the context of immunogenicity and lysosomal storage disorders were highlighted. In this study, the effects of excess anti-drug antibodies on clinical outcomes in male patients with Fabry disease receiving enzyme replacement therapy were investigated. Patients with excess anti-drug antibodies during therapeutic infusion exhibited progressive loss of extracellular glomerular filtration rate and ongoing cardiac hypertrophy.⁴⁶ These effects were not observed in patients with Fabry disease who had achieved therapeutic protein/antibody equilibrium following infusion with enzyme replacement therapy. Consequently, the results of this study emphasise the need for more personalised treatment of patients with Fabry disease as the development of anti-drug antibodies may affect clinical response to therapeutic interventions.⁴⁶

The second presentation was delivered by Dr Stefaan Sansen (Rare Diseases, Sanofi Genzyme, Brussels, Belgium) who focused on strategies for diagnosis of rare diseases. In Dr Sansen’s own words, he described the challenges that can complicate rare disease diagnoses. These included low disease awareness, non-specific disease symptoms, lack of infrastructure for diagnostic testing and variable access and differences in testing strategies. Recommendations of a diagnostic test should aim to be based on evidence from randomised clinical trials, where the strategies are compared using patient-relevant outcomes.⁴⁷ However, in the field of rare diseases, Dr Sansen highlighted that, in his opinion, cross-sectional and case-control studies are typically used when assessing the accuracy of diagnostic tests. However, use of case-control studies, in which patients with an established disease diagnosis are compared with a healthy control group, may lead to inflated estimates of accuracy when testing a new diagnostic strategy.⁴⁸ Instead, cross-sectional studies include individuals who have a suspected diagnosis. In these studies, the new diagnostic strategy is tested initially, followed by the index test, which would typically be used to make a diagnosis.⁴⁸ Dr Sansen then described a cross-sectional study that investigated the clinical utility of the biomarker globotriaosylsphingosine (lyso-Gb₃) in diagnosing female patients with Fabry disease. Measurement of alpha-galactosidase A (α-Gal A) enzyme levels in addition to levels of lyso-Gb₃ in dried blood spots was shown to enhance the diagnostic detection of Fabry disease in the 11,948 females included in the study. Abnormal levels of both α-Gal A and lyso-Gb₃ were described as ‘highly suspicious’ indicators of Fabry disease (97% positive predictive value), whereas in cases where only one biochemical value was abnormal, levels of lyso-Gb₃ were more indicative of Fabry disease diagnosis compared with α-Gal A (positive predictive values: 39% and 6%, respectively). Normal levels of both α-Gal A and lyso-Gb₃ were considered unlikely to be associated with Fabry disease diagnosis.⁴⁹ Dr Sansen indicated that the results of this cross-sectional study were externally validated in a separate publication. In this study, the positive predictive value of peripheral blood samples of lyso-Gb₃ in confirming a diagnosis of Fabry disease was 100% in both males and females, compared with 84% and 58% in males and females, respectively, using assessments of α-Gal A enzyme activity.⁵⁰ Dr Sansen concluded his presentation by highlighting that, in his opinion, diagnostic strategy accuracy should be taken into account during decision-making in clinical practice, and that this information may be derived from large cross-sectional studies.

The final presentation was given by Dr Amanda Wilson (Real World Evidence, Sanofi Genzyme, Cambridge, MA, USA), who firstly described the difficulties associated with diagnosing rare diseases and the potential of artificial intelligence in aiding diagnoses. In her opinion, the low prevalence, disease heterogeneity and the lack of knowledge of disease natural history can lead to misdiagnosis and under-diagnosis of lysosomal storage disorders, which could ultimately affect patient outcomes. Dr Wilson noted that, in her experience, real-world data have been used to help elucidate the pathway to diagnosis of patients with lysosomal storage disorders. Examples of real-world data, as outlined by Dr Wilson, may include international patient registries, observational studies and case series, which are all typically based on disease-specific datasets.⁵¹ From Dr Wilson’s viewpoint, the current real-world data on lysosomal storage disorders are limited as they are based on disorder-specific databases and do not include, for example, information from administrative claims databases or electronic health records. However, some examples do exist.^52-54 Dr Wilson then noted that, from her perspective, the historical limitations associated with use of current real-world data in lysosomal storage disorders may be overcome by using information from electronic health records and artificial intelligence. Using this large volume of patient information from a large number of patients across a variety of clinics may allow greater integration of patient data. Development of algorithms, or artificial intelligence, and analysis of patient data from electronic health records may lead to the identification of a greater number of disease features, as described by Dr Wilson. These diagnostic algorithms can then be tested on other datasets and used in other clinics or countries. In her opinion, the use of artificial intelligence is yet to be impactful in the field of lysosomal storage disorders; however, using data modelling and algorithms based on electronic health records may lead to:

• Greater identification of patients at risk of a lysosomal storage disorder
• Recognition of the most common disease characteristics experienced by patients with lysosomal storage disorders and a comparison of diagnosed versus undiagnosed patients
• Earlier detection of patients with an undiagnosed lysosomal storage disorder.

Satellite symposium supported by Amicus Therapeutics, Inc.
Dr Robert Hopkin (Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA) opened the satellite symposium by providing a general background on Fabry disease. Next, Dr Fabian Braun (University Medical Center Hamburg – Eppendorf, Hamburg, Germany) provided a general overview of lysosomal functioning. Lysosomes are considered integral for homeostasis and the overall dynamics of the entire cell, and, from Dr Braun’s viewpoint, the level of understanding of lysosome function has dramatically increased over time. He noted that the underlying mechanisms of lysosomes are now recognised as much more complicated than initially thought, with most processes being highly regulated. Autophagy is among the several functions that lysosomes serve within cells,¹ and Dr Braun highlighted one study in which a human podocyte model of Fabry disease revealed that dysregulation of autophagy pathways was associated with defective lysosomal enzymatic activity in patients.⁵⁵ In Dr Braun’s opinion, advancing understanding of lysosomal signalling and functioning may enable the development of targeted therapies for Fabry disease and may enhance treatment strategies for other lysosomal storage disorders.

Dr Guido Laccarino (University of Naples, Naples, Italy) next described the multisystemic impact Fabry disease has on organs throughout the body, noting that the heart is often affected and associated with an alteration in the vasculature.⁵⁶ He highlighted that alterations in mitochondrial functioning can lead to pathophysiological myocardial remodelling and subsequently heart failure.⁵⁷ In Dr Laccarino’s opinion, restoration of mitochondrial function via a rescue-like mechanism in the mitochondrial lifecycle may be of clinical benefit to patients with Fabry disease and cardiac manifestations.

Next Dr Soumeya Bekri (Rouen University Hospital, Rouen, France) provided further insight into the pathophysiological mechanisms associated with Fabry disease by discussing developments in the assessment and identification of biomarkers for clinical diagnosis and monitoring. She noted that characteristics of good biomarkers, as supported by those developed for cancer, may include whether they are quantifiable, sensitive and specific, correlative to a clinical outcome, have the ability to stratify the risk of progression, cost-effective and enable tailored patient management.⁵⁸ She noted that introduction of biomarkers into the diagnosis and monitoring framework for Fabry disease using proteomics-based methodologies has elucidated predictable biological patterns that provide enhanced insight into the disease. For example, in one study, clear distinctions in molecular profiles were observed between plasma samples of patients with Fabry disease and healthy unaffected individuals.⁵⁹ Four discriminant proteins were identified between samples: fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC) and interleukin-7 (IL-7). Moreover, levels of FGF2 and IL-7 were elevated in patients with Fabry disease.⁵⁹ Dr Bekri highlighted that further analysis indicated each of the four identified proteins were associated with specific clinical manifestations related to Fabry disease, namely⁵⁹:

• FGF2: arrhythmia, arterial thrombosis, cornea verticillata, neuropathic pain, phenotype and stages of chronic kidney disease
• VEGFA: angiokeratoma, cardiac score, cornea verticillata, neuropathic pain, stroke and venous thrombosis
• VEGFC: arrhythmia, cardiac score, stages of chronic kidney disease, stroke and thrombosis
• IL-7: arterial thrombosis, cardiac score, chronic kidney disease, cornea verticillata, hypertrophic cardiomyopathy, neuropathic pain and sudation disorder.

In Dr Bekri’s opinion, further development of proteomics-based technology and bioinformatics may enhance exploration of Fabry disease biomarkers, thereby enabling clinicians to further tailor treatment to the needs of their patients.

In the final section of the satellite symposium, Dr Hopkin outlined his clinical perspectives of treating Fabry disease early in the disease course. He noted that, from his perspective, treatment of the disease as early as possible (i.e., at the first presentation of symptoms) is ideal. In Dr Hopkin’s opinion, diagnosis of Fabry disease is challenging as symptoms may be associated with more common conditions. From his perspective, early signs and symptoms of Fabry disease may be non-specific, and the clinician may have to actively think outside the normal diagnostic framework to arrive at a diagnosis of Fabry disease. Once diagnosed, Dr Hopkin indicated that from his clinical experience, follow-up and monitoring leads to better clinical outcomes for patients with Fabry disease. A clinician experienced in Fabry disease, with input from a cardiologist, genetic counsellor, medical geneticist, nephrologist, neurologist, nurse and psychologist, is considered appropriate to supervise follow-up assessments and treatment throughout a patient’s life.²⁴

Satellite symposium supported by AVROBIO, Inc.
Dr Dominique P Germain (APHP – University Paris Saclay, Paris, France) began by indicating that the focus of this satellite symposium was considerations for treatment of lysosomal storage disorders with lentiviral gene therapy. Firstly, Dr Robert J Hopkin (Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA) discussed the current standard of care for patients with lysosomal storage disorders. Next, Dr Hopkin described lentiviral gene therapy, which is a treatment under investigation for patients with lysosomal storage disorders.

Lentiviral gene therapy has been shown to target numerous cell types within the body stemming from erythroid, lymphoid system and myeloid lineages.⁶⁰ Dr Paul J Orchard (University of Minnesota, Minneapolis, MN, USA) continued the presentation by describing the approach for using lentiviral gene therapy in patients with lysosomal storage disorders. He also highlighted the potential relative advantages of the treatment compared with allogeneic haematopoietic stem cell therapy. For example, one inherent advantage of lentiviral gene therapy is that it utilises autologous cells, resulting in a low risk of graft failure and limited risk of graft versus host disease.^61,62 Dr Orchard next described conditioning, which helps to deplete resident progenitor and stem cells, allowing for the transplantation of the patient’s transduced stem cells.⁶⁰ To achieve this depletion of resident stem cells, Dr Orchard described busulfan therapy, which serves to condition the brain and body prior to lentiviral gene therapy.⁶³ Dr Orchard did note that longer follow-up of this process is required; however, preliminary evidence suggests that normal or above normal levels of functional enzyme, arylsulfatase A, may be achieved in patients conditioned with busulfan prior to receiving lentiviral gene therapy, as demonstrated in children with metachromatic leukodystrophy.⁶⁴

Next Dr Brian Bigger (University of Manchester, Manchester, UK) focused on areas under investigation to improve delivery of functional enzyme after lentiviral gene therapy. Potential clinical avenues for achieving this include increases in: (1) enzyme production and release through transgene supraphysiological expression; (2) cell trafficking using agents such as busulfan; (3) enzyme blood–brain barrier passage via peptide tags; and (4) enzyme circulation and stability through improvements in enzyme peptide tags.⁶⁵

To conclude, Dr Germain summarised the key take-home messages from this satellite symposium, from his perspective and from the literature:

• One advantage of lentiviral gene therapy is the utilisation of autologous haematopoietic stem cell transplantation^61,62
• The usefulness of lentiviral gene therapy may be improved through prior conditioning, which allows the modified stem cells to engraft^60,63
• Normal or above normal levels of functional enzyme, arylsulfatase A, have been observed with lentiviral gene therapy in children with metachromatic leukodystrophy.⁶⁴

Dr Peter Marks (Center for Biologics Evaluation and Research, US Food & Drug Administration, Silver Spring, MD, USA) began this keynote address by highlighting the need for individualised treatment using gene therapy for patients with rare diseases. He indicated that one study has shown that direct systemic administration of a gene therapy has demonstrated efficacy in children with spinal muscular atrophy type 1.⁶⁶ Dr Marks noted that he hoped the success of gene therapy shown in this study can be reproducible in other diseases. However, in Dr Marks’ opinion, there are still some unknowns with gene therapy, including how broadly applicable a treatment is for different disease phenotypes and how long the effects of gene therapy will last in patients. Next, Dr Marks discussed the concept of individualised medicine. In his own words, he described individualised medicine as the creation of a drug to treat a patient. He further noted that, from this perspective, individualised medicine can either be customised to the patient – one drug with the same mode of action used for the same indication – or alternatively, individualised medicines can be created for different indications with a different mode of action, e.g., the use of gene therapies for two separate variants using the same vector backbone. Dr Marks noted that, in his experience, science is typically more familiar with customised medicines; however, the path to created medicines may be described as ‘trailblazing.’ In Dr Marks’ opinion, there may be some challenges associated with individualised therapies, including the non-clinical and clinical development of these medicines, and also manufacturing and eventually treatment access for patients. Additionally, clinical development of gene therapies could be described as challenging, as documenting the natural history of a disease may be difficult and, in some cases, the disease population may be small. Therefore, in Dr Marks’ opinion, templates for collecting baseline data or new clinical trial designs may be necessary for gene therapies to be assessed effectively during clinical development. Finally, Dr Marks highlighted that, from his viewpoint, the use of gene therapies could be limited by patient access and large-scale production. To conclude, Dr Marks emphasised that, from his experience, the development of cell and gene therapies for patients with rare diseases is advancing and ongoing work is aiming to overcome the limitations in current manufacturing to help the individualisation of medicine.

Satellite symposium supported by Sanofi Genzyme
Firstly, Dr Juan Politei (Fundación para el Estudio de las Enfermedades Neurometabólicas, Buenos Aires, Argentina) began by describing the clinical spectrum of Fabry disease. Manifestations of Fabry disease in early life are typically associated with the classical phenotype, whereas the late-onset phenotype can present in older patients.²⁴ Dr Politei then went on to discuss the current understanding of the clinical spectrum of symptoms observed in female patients. Enzymatic activity of alpha-galactosidase A (α-Gal A) can vary depending on the level of X-chromosome inactivation of the GLA gene.⁶⁷ Next, Dr Politei discussed the use of globotriaosylsphingosine (lyso-Gb₃) as a biomarker for Fabry disease. Lyso-Gb_­3­ has been described as a reliable diagnostic tool to distinguish between patients with classical Fabry disease and healthy unaffected individuals; however, it is considered less useful in identifying female patients due to the overlap with lyso-Gb₃ levels in unaffected individuals.⁶⁸

Dr Alberto Ortiz (Fundación Jiménez Díaz, University Autónoma de Madrid, Madrid, Spain) then discussed some of the advances in nephrology in Fabry disease. He noted that podocyte injury, in parallel with podocyte lyso-Gb₃ accumulation and proteinuria, are associated with the development and progression of Fabry nephropathy.⁶⁹ Podocyte loss has been linked to adverse renal outcomes in patients with Fabry disease, highlighting the need for therapeutic intervention before podocyte loss occurs.⁷⁰ Dr Ortiz then went on to discuss treatment goals for renal symptoms in patients with Fabry disease. In one study of 20 patients with classical Fabry disease, long-term treatment with enzyme replacement therapy dose was found to correlate with podocyte lyso-Gb₃ reduction.⁷¹ Therefore, Dr Ortiz suggested that reducing lyso-Gb₃ accumulation in podocytes may be a therapeutic goal for patients with Fabry disease.⁷²

Next, Dr Mehdi Namdar (Geneva University Hospital, Geneva, Switzerland) discussed some of the advances in cardiology research in Fabry disease. Dr Namdar highlighted that cardiovascular disease may be a major driver of mortality in patients with Fabry disease.^73,74 Treatment of Fabry disease with enzyme replacement therapy has been associated with improved cardiac function and patients treated prior to cardiac symptoms may have a better prognosis in multiple measures of cardiac function.^75,76 Dr Namdar then went on to discuss ongoing research into the early stages of cardiac involvement in Fabry disease. These techniques include detection of sphingolipid storage using cardiovascular magnetic resonance and electrocardiogram (ECG) analysis prior to the development of left ventricular hypertrophy, or screening for cardiac contractile dysfunction using an artificial intelligence-enabled ECG.^77,78

Satellite symposium supported by an independent educational grant from Takeda
This satellite symposium was chaired by Dr Uma Ramaswami (Institute of Immunity and Transplantation, London, UK), who opened the session by providing a general overview of the role of inflammation in lysosomal storage disorders and strategies for treatment.

In the first presentation by Dr Ozlem Goker-Alpan (Lysosomal and Rare Disorders Research and Treatment Center, Fairfax, VA, USA), she described the role of inflammation in Gaucher disease and highlighted that glucosylceramide and glucosylsphingosine (lyso-Gb1) can trigger an immune and inflammatory response.⁷⁹ She went on to discuss results from a clinical study in patients with Gaucher disease treated with enzyme replacement therapy, which showed that only partial rescue of immune dysregulation was achieved.⁸⁰ However, she explained that a subanalysis of the results demonstrated that an improved rescue of the immune response could be achieved in those patients who were diagnosed and treated early with enzyme replacement therapy.⁸⁰

The second presentation of the satellite symposium was by Dr Troy Lund (University of Minnesota, MN, USA), who discussed inflammation in metachromatic leukodystrophy disease. He provided evidence that in patients with metachromatic leukodystrophy disease, there was an increase in the levels of cytokines, including MCP-1, in the cerebrospinal fluid of patients compared with healthy controls, which indicated inflammation.⁸¹ He went on to highlight that there was a significant correlation between the MCP-1 levels in the cerebrospinal fluid and plasma levels of those patients with metachromatic leukodystrophy disease, which he hypothesised indicates that the cytokine MCP-1 could be a potential marker for inflammation.⁸¹ Dr Lund continued by explaining that in one patient with metachromatic leukodystrophy disease who had received a haematopoietic cell transplant, cytokine levels, including MCP-1, were reduced post-haematopoietic cell transplant, which he speculated could mean that the haematopoietic cell transplant may have led to partial attenuation of the inflammatory response.⁸¹

The final presentation was by Dr Lynda Polgreen (The Lundquist Institute, Harbor-UCLA Medical Center, Torrance, CA, USA), who discussed inflammation and treatment strategies for patients with mucopolysaccharidoses. Dr Polgreen provided evidence that in rat models of mucopolysaccharidosis type VI, enzyme replacement therapy alone did not reduce synovial inflammation in knee joints.⁸² In contrast, evidence suggests that in rats treated with enzyme replacement therapy and rat-specific anti-TNF-α, inflammation and formation of villi were markedly reduced.⁸² She went on to explain that an increase in TNF-α levels in patients with mucopolysaccharidosis types I, II and VI is associated with increased pain and decreased physical function.⁸³ Dr Polgreen suggested that anti-inflammatories, such as TNF-α inhibitors, may be a potential adjunctive therapy for the treatment of mucopolysaccharidosis.⁶

Satellite symposium supported by Chiesi USA Inc.
Ms Dawn Laney, CGC (Emory University School of Medicine, Atlanta, GA, USA) began this satellite symposium by providing an overview of the known disease pathology for COVID-19. Ms Laney then described how the pathogenesis of severe disease associated with COVID-19 and Fabry disease may overlap, with risk factors including severe kidney disease, cardiovascular disease, lung disease, endothelial dysfunction with potential for thrombosis, and systemic inflammation.⁸⁴ In one real-world study conducted across four countries, 22 patients with Fabry disease and COVID-19 were included and the severity of disease was assessed; results showed that four patients experienced moderate and two patients experienced critical disease. Those who had critical COVID-19 disease were aged ≥59 years and had Fabry disease-associated cardiac and/or renal symptoms. Patients with Fabry disease who had either moderate or critical COVID-19 disease severity experienced COVID-19 symptomatology for ≥7 days. Assessment of severe COVID-19 disease risk in patients with Fabry disease in this study indicated that in alignment with the general population, pre-existent tissue injury and inflammation may predispose patients with advanced Fabry disease symptom severity to develop a more severe course of COVID-19 disease. These findings highlight the recommendations for clinicians to reinforce all COVID-19–related safety precautions to patients with Fabry disease.⁸⁴

Dr Jaya Ganesh (Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA) then discussed how COVID-19 affects similar organ systems that may be experienced by patients with Fabry disease. She described how renal impairment, a common manifestation of Fabry disease,⁸⁵ has been identified as a risk factor for COVID-19–related death,⁸⁶ thereby possibly increasing the likelihood of patients with Fabry disease being disproportionately impacted. Additionally, individuals with cardiovascular disease were identified as being at greater risk of death due to COVID-19 early in the pandemic.⁸⁷ Cardiovascular disease may be a major cause of mortality in patients with Fabry disease,^73,74 and in one study of 73 patients, 27% experienced malignant ventricular arrhythmias and 10% experienced sudden cardiac death.⁸⁸ Dr Ganesh then discussed how inflammatory processes potentially play a role in whether patients with COVID-19 experience poor outcomes as SARS-CoV-2 has been shown to evoke an immune response via upregulation of proinflammatory cytokines and chemokines in human lung tissue.⁸⁹ Inflammatory biomarkers are elevated in patients with Fabry disease and correlate with disease progression, suggesting a key pathogenic role of systemic inflammation.⁹⁰ Dr Ganesh concluded this satellite symposium by highlighting that it is recommended that diagnosis of Fabry disease does not prevent providing full therapeutic support as required for patients who develop COVID-19–associated disease.⁸⁴