Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease

Donald et al. Orphanet Journal of Rare Diseases (2022) 17:234 https://doi.org/10.1186/s13023-022-02378-7 Open Access RESEARCH Thirty‑year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease Aimee Donald1* , Cecilia Kämpe Björkvall2, Ashok Vellodi4, GAUCHERITE Consortium5, Timothy M. Cox6, Derralyn Hughes7, Simon A. Jones1, Robert Wynn3 and Maciej Machaczka8,9 Abstract Background: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood–brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder. Results: In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes. Conclusions: Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous—especially where sustained provision of highcost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches. Keywords: Neuronopathic Gaucher disease, Type 3 Gaucher disease, HSCT, BMT, Neurology, Outcomes *Correspondence: 1 Manchester Centre for Genomic Medicine, St Marys Hospital, Manchester, UK Full list of author information is available at the end of the article Background Gaucher disease (GD) is a lysosomal storage disorder (LSD) caused by pathogenic variants in the GBA gene (OMIM: 60646) that reduce activity of the lysosomal © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Donald et al. Orphanet Journal of Rare Diseases (2022) 17:234 enzyme acid β-Glucosylceramidase. The disease is inherited as an autosomal recessive trait and classified by phenotype with traditional categorisation that depends on the presence or absence of neurological signs, most specifically the presence of slow horizontal saccades. Types ‘2’ and ‘3’ are regarded as neuronopathic (nGD); “acute” and “chronic” respectively. Infants die before childhood in the acute form of the disease and those with the chronic form, have a slowly progressive neurological disease characterised by cerebellar dysfunction, motor impairment and in some, development of seizures and myoclonus; a recent consensus definition of nGD offers clarification [1]. The systemic aspects of the disease affect all patients but until recently were considered to be the sole manifestations of ‘type 1’ disease—in which patients present with hepatosplenomegaly, a predominant thrombocytopenia (although pancytopenia occurs), bone disease and infiltration of other organs by pathological macrophages. More recently, the appearance of Parkinson disease [2] and Lewy-body dementia in a minority of patients previously classified as having type 1, nonneuronopathic Gaucher disease, has confounded the categorical clinical sub-typing. Gaucher disease is one of more than 80 LSDs but is a paradigm for understanding disease mechanisms as well as the development of molecular and cellular therapy in the current era: it was one of the earliest to be characterised clinically and, from the aspect of biochemical genetics and introduction of disease-modifying treatment, is in the vanguard of contemporary therapeutics. Catalytic deficiency of β-Glucosylceramidase causes accumulation of glycosphingolipid substrates (glucosylceramide and glucosylsphingosine) in the lysosomal compartment of many cells but the molecular processes that lead to tissue injury and cell death are not understood. Many of the systemic features affect organs rich in tissue macrophages which acquire excess glucosylceramide from the engulfment and incomplete lysosomal breakdown of sphingolipids derived exogenously from other cells, especially leukocytes; the consequential enlarged pathological ‘storage’ macrophages are known as Gaucher cells and are prominent in the bone marrow, liver, and spleen. However, neuropathological studies have f (...truncated)