The WorldSymposiumTM sessions began on Thursday 11 February with a keynote address from Dr Peter Marks (Center for Biologicals Evaluation and Research, US Food & Drug Administration, Silver Spring, MD, USA) where he discussed a regulatory framework for individualised therapies. This session was followed by satellite symposia on the impact of inflammation in lysosomal storage diseases and gene therapy for Gaucher disease.

Contemporary forum and satellite symposia

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 1.1 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 mutations 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 individualisation of medicine.

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 diseases 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.2 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.3 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.3

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 cytokine levels, including MCP-1, in the cerebrospinal fluid of patients compared with healthy controls, which indicated inflammation.4 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.4 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.4

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.5 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.5 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.6 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 AVROBIO, Inc

Dr Timothy Cox (University of Cambridge, Cambridge, UK) chaired this satellite symposium, which aimed to describe the patient experience and unmet needs, and the relationship of Parkinson’s disease and Lewy body disease with Gaucher disease Type 1. The new development of lentiviral gene therapy was also discussed. Firstly, Ms Cyndi Frank (Co-founder and Co-president of the Gaucher Community Alliance) gave an overview of the patient experience of Gaucher disease Type 1, beginning with the potential challenges and impact on quality of life. She explained how misdiagnosis of Gaucher disease Type 1 is common due to diagnostic delays.7 She went on to highlight that the symptoms of Gaucher disease Type 1 may affect both the personal and professional life of patients, and that, in her opinion, the mental health of these patients has not been addressed sufficiently. Patients with Gaucher disease may suffer from depression and the prospect of neurological deficits later in life may weigh heavy on them.8,9 She explained that when looking at new treatment options for Gaucher disease Type 1, the meaningful improvements desired by patients may relate to10,11:

  • A significant improvement in all symptoms and quality of life
  • Slowing or stopping disease progression
  • Reduction of neurological symptoms or disease risk (e.g. Parkinson’s disease)
  • Reduced impact on daily living (e.g., time lost due to pain or fatigue or time needed for enzyme replacement therapy infusions).

Ms Frank stated that, from her perspective, investigational lentiviral gene therapy may provide hope for the Gaucher disease community, and that patient involvement in clinical trials is a personal decision, with both barriers (e.g., unknown benefits, potential risks and demands of being in a trial) and benefits (e.g., access to investigational therapy and monitoring at a centre of excellence).

Next, Dr Cox gave an overview of Gaucher disease Type 1, from its discovery and pathology to the current treatments and unmet needs. He described the case of a child who died from Gaucher disease in Pakistan due to no access to therapy, highlighting that, in his opinion, there is an unmet need to provide treatment access to patients with Gaucher disease Type 1 worldwide. Dr Roy Alcalay (Columbia University Medical Center, New York, NY, USA) continued with a presentation on the link between Gaucher disease, Parkinson’s disease and Lewy body disease. Dr Alcalay described the genetic overlap between Gaucher disease and Parkinson’s disease; in a study by Sidransky et al (2009)12 among Ashkenazi Jewish patients with Parkinson’s disease, N370S or L444P glucocerebrosidase (GBA) gene mutations was found in 15% of patients and 3% of controls, whilst in non-Ashkenazi Jewish patients with Parkinson’s disease, either mutation was found in 3% of patients and <1% of controls. He went on to explain that in the same study, a total of 20% of Ashkenazi Jewish patients and 7% of non-Ashkenazi Jewish patients were found to carry a GBA mutation.12 In a second study by Gan-Or et al (2015), he presented results which showed that the observed frequency of severe GBA mutation carriers among Ashkenazi Jewish patients with Parkinson’s disease was more than 4-times greater than expected (4.4% vs 0.9%).13 He highlighted that most patients with Gaucher disease will not develop Parkinson’s disease.14 However, the risk factors associated with developing Parkinson’s disease in patients with Gaucher disease are being male (p=0.027) and of older age (p=0.004). Risk factors specific to Gaucher disease, such as disease severity, splenectomy and use of enzyme replacement therapy, are not associated with the development of Parkinson’s disease (p=0.60, p=0.40 and p=1.00, respectively).14 Dr Alcalay also described how up to 1% of Ashkenazi Jewish patients with Parkinson’s disease also have Gaucher disease but they may not know it. In one study, out of a total of 1050 Ashkenazi Jewish patients with Parkinson’s disease, 12 were homozygotes or compound heterozygotes for mutations in the GBA gene. Compared with GBA carriers with Parkinson’s disease and idiopathic Parkinson’s disease, these patients had a higher prevalence of rapid eye movement, sleep behaviour disorder and hallucinations, as well as an earlier age at onset, more severe motor impairment, poorer cognition and lower olfactory scores.15 Then, Dr Alcalay explained that GBA mutations are strongly associated with Lewy body dementia risk, which is stronger than the risk between having Gaucher disease and developing Parkinson’s disease.16 However, no study to date has estimated the risk for Lewy body disease in patients with Gaucher disease. In Dr Alcalay’s opinion, there is an unmet need for clinical research in this field, and he highlighted that there was a lack of good estimation of the age-specific risk for Parkinson’s disease and Lewy body disease among patients with Gaucher disease, and on whether current or future treatments modify this risk.

In the final presentation, Dr Aneal Khan (University of Calgary, Alberta, Canada) gave an overview of gene therapy and described an experimental ex vivo lentiviral gene therapy for Gaucher disease Type 1.


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/0027; Date of preparation: February 2021