The WorldSymposiumTM sessions on Sunday 7 February brought together healthcare professionals and researchers from across the world to attend a state-of-the-art expert review of the recent advances in lysosome biology, rare diseases, therapies, and COVID-19 in the context of lysosomal disorders. Dr Chester B Whitley (University of Minnesota, Minneapolis, MN, USA) opened the session and provided an introduction and overview of the course.
Emerging Trends: State-of-the-Art for Experts
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 diseases may be associated with a continuum of disease severity. In his opinion, the concept of lysosomal storage diseases and lysosomal functioning has evolved. He highlighted that lysosomes have multiple roles within a cell, and accumulation of storage material associated with lysosomal storage diseases can affect autophagy, cell viability, exocytosis, lipid homeostasis, membrane repair and signalling cascades, which are linked to lysosomal functioning.1 He then went on to describe 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 diseases are characterised by multi-organ pathology caused by mutations in the genes encoding lysosomal enzymes and proteins.2 Further research into lysosomes has shown that impairment of lysosomal growth and catabolic processes has 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 diseases 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 diseases 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 disease, 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 disease; 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 disease. 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 diseases. 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 disease diagnosis is the product of a patient’s phenotype (based on clinical and imaging data), biochemistry (assessment of enzyme and biomarker levels) and gene mutations. Dr Patterson concluded his presentation by restating that the ‘traditional’ approach to diagnosis of lysosomal storage diseases 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, that 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?
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 diseases. 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 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; and 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 diseases 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 diseases. In addition, patients with multi-systemic clinical manifestations may have a higher risk for COVID-19–related complications. Based on her clinical experience, Dr. Lau made several recommendations for managing patients with lysosomal storage diseases 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 diseases, and a risk-reduction strategy is recommended to be tailored to each patient, with management of the disease continuing throughout the pandemic.
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/0023; Date of preparation: February 2021
- Marques ARA, Saftig P. Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases. J Cell Sci 2019; 132.
- Platt FM, d'Azzo A, Davidson BL, et al. Lysosomal storage diseases. Nat Rev Dis Primers 2018; 4: 27.
- Lawrence RE, Zoncu R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol 2019; 21: 133-142.
- Andermann A, Blancquaert I, Beauchamp S, et al. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ 2008; 86: 317-319.
- Wilson J, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968. Available at: https://apps.who.int/iris/handle/10665/37650. Accessed February 2021.
- Health Resources & Services Administration. Recommended Uniform Screening Panel. Available at: https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html. Accessed February 2021.
- U.S. Food and Drug Administration. The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective. Available at: https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective. Accessed February 2021.
- U.S. Food and Drug Administration. New Drug Application (NDA). Available at: https://www.fda.gov/drugs/types-applications/new-drug-application-nda. Accessed February 2021.
- U.S. Food and Drug Administration. Guidance for Industry: E 10 Choice of Control Group and Related Issues in Clinical Trials. Available at: https://www.fda.gov/media/71349/download. Accessed February 2021.
- U.S. Food and Drug Administration. Surrogate Endpoint Resources for Drug and Biologic Development. Available at: https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development. Accessed February 2021.
- U.S. Food and Drug Administration. Clinical Outcomes Assessment Development and Implementation: Opportunities and Challenges Public Workshop. Presented at: PDUFA V, 2015; FDA, White Oak Campus, Silver Spring, MD, USA.
- Sacristán JA, Aguarón A, Avendaño-Solá C, et al. Patient involvement in clinical research: why, when, and how. Patient Prefer Adherence 2016; 10: 631-640.
- Chalasani M, Vaidya P, Mullin T. Enhancing the incorporation of the patient's voice in drug development and evaluation. Res Involv Engagem 2018; 4: 10.
- Porter KA, O'Neill C, Drake E, et al. Parent experiences of Sanfilippo syndrome impact and unmet treatment needs: a qualitative assessment. Neurol Ther 2020; Epub ahead of print.
- World Health Organization. Timeline: WHO's COVID-19 response. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/interactive-timeline#. Accessed February 2021.
- Clinical Care Options. COVID-19 Comprehensive Resource Center. Available at: https://www.clinicaloptions.com/pulmonology/programs/covid19-resources. Accessed February 2021.
- Nextstrain. Nextstrain SARS-CoV-2 resources. Available at: https://nextstrain.org/sars-cov-2/. Accessed February 2021.
- Centers for Disease Control and Prevention. Symptoms of Coronavirus. Available at: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Accessed February 2021.
- Carfì A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute COVID-19. JAMA 2020; 324: 603-605.