Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β‐precursor and the γ‐subunit of N‐acetylglucosamine (GlcNAc)‐1‐phosphotransferase, respectively, the key enzyme for the generation of mannose 6‐phosphate targeting signals on lysosomal enzymes. Defective GlcNAc‐1‐phosphotransferase results in missorting of lysosomal enzymes and accumulation of non‐degradable macromolecules in lysosomes, strongly impairing cellular function. MLII‐affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc‐1‐phosphotransferase, but also helped to define genotype‐phenotype correlations to predict the clinical outcome in patients.
Background Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. Results We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT—multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. Conclusion We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
Autologous ex vivo hematopoietic stem cell gene therapy is particularly relevant in lysosomal storage diseases (LSD) as it offers the prospect of both a safe transplant, as observed in immune deficiency and hematologic illness, and an effective transplant, since it delivers greater enzyme levels to host tissues than is possible in allogeneic transplant. We report early data from such an approach in an allogeneic transplant refractory LSD, Mucopolysaccharidosis type IIIA (MPSIIIA, Sanfilippo syndrome). Background: MPSIIIA is a LSD caused by mutations in the SGSH gene leading to a deficiency of the enzyme N-sulfoglucosamine sulfohydrolase. As a result there is accumulation of heparan sulfate, with clinical manifestations of developmental delay, regression of previously acquired skills, hyperactivity, seizures and progressive cognitive decline leading to an early death at the end of the second decade of life. Unlike some other LSDs, MPSIIIA is unresponsive to allogeneic stem cell transplant (Hoogerbrugge et al., The Lancet 1995; Sivakumur & Wraith, Journal of inherited metabolic disease 1999), with the donor cells unable to deliver enough enzyme for clinically meaningful cross-correction. Significant pre-clinical work undertaken at the University of Manchester led to the design of the lentiviral vector containing the SGSH gene and a CD11b (myeloid) promoter. In murine studies MPSIIIA mice underwent stem cell mobilization and collection and stem cells were transduced with the lentiviral vector ex vivo. The mice received myeloablative busulfan before being infused with the autologous transduced stem cells. Enzyme expression in the brain was high with normalised heparan sulfate and improvement in the behavior of the mice (Sergijenko et al., Molecular Therapy 2013). Transduction and transplant of human CD34+ stem cells to humanized NSG mice demonstrated stable engraftment with no evidence of viral shedding or transformational potential (Ellison et al., Molecular Therapy-Methods & Clinical Development 2019), further adding to the safety profile and the translation of this work to the clinic. Study Design and Methods: This is a phase I/II safety and tolerability study. It is open-label and aims to recruit up to 5 patients. Patients enrolled into the trial are between the age of 3 and 24 months, have confirmed classical MPSIIIA (either by known genotypes, somatic features or family history) and have preserved neurocognitive function (DQ ≥80) before commencing the trial. Patients undergo stem cell mobilization and peripheral collection of CD34+ cells. The SGSH gene under the CD11b promoter is introduced by the lentiviral vector. Patients then receive myeloablative busulfan before infusion of the autologous transduced stem cells. Follow up takes place over 3 years. The primary end point is to assess the safety and tolerability of the transduced stem cell product. The primary efficacy endpoint is SGSH activity in leukocytes at 12 months. Several secondary and exploratory end points are also to be reported including neurocognitive outcomes. Current trial status: We report the preliminary data of the first treated patient recruited to the trial including the mobilization, transplant and sustained engraftment of gene-modified cells by vector copy number. Supra-physiological enzyme expression in multiple lineages - 150 fold increase above median in leukocytes and 200 fold increase above control in myeloid lineage - and substrate reduction in plasma, CSF and urine - reduced in urine to normal range by 3 months - has been observed. Disclosures Bigger: Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thrasher:Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jones:Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
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