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.
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.
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.
Abstract Background Quality measurement in palliative care requires robust data from standardized data collection processes. We developed and tested the feasibility of the Quality Data Collection ...Tool version 1.0 (QDACTv1.0) for use in community-based palliative care. Measures To evaluate for implementation barriers, we tested feasibility, acceptability, and utility of the QDACTv1.0 by reviewing use patterns, surveying clinician users, and reporting conformance with quality metrics. Intervention Comprising 37 questions within five domains, QDACTv1.0 was launched in May 2008 for data collection at point of care. Outcomes Through March 2011, data on 5959 patients in 19,734 visits have been collected. We observed steady quarterly growth in data collection, positive clinician feedback, and successful mapping of data to quality metrics. Information gathered characterized practice variations and suggested quality improvement initiatives. Clinician feedback has driven updating to Quality Data Collection Tool version 2.0. Conclusions/Lessons Learned Standardized data collection is feasible in routine community-based palliative care and is valuable for quality monitoring.
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.
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.
The excretory–secretory product (ESP) derived from Cyathostominea in vitro was assessed, in terms of subunit composition, and proteolytic activity using as substrates azocasein and two synthetic ...fluorogenic peptides. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) resolved 13 subunits, and the presence of the protein cysteine proteinase activator dithiothreitol (DTT) revealed 21 subunits. DTT also enhanced azocaseinolysis, and hydrolysis of carbobenzoxy-phenylalanyl-arginine-7-amido-4-methylcoumarin (Z-Phe-Arg-NHMec) and carbobenzoxy-arginyl-arginine-7-amido-4-methylcoumarin (Z-Arg-Arg-NHMec). At the optimum pH of 5.5, hydrolysis of Z-Phe-Arg-NHMec was three-fold greater than that of Z-Arg-Arg-NHMec suggesting that the proteolytic specificities of the ESP are more like those of papain or cathepsin L, rather than cathepsin B. In SDS-PAGE gelatin gels, DTT was a requirement for proteolysis by the ESP. Optimum resolution was at pH=5.5, resolving six bands ranging from 114–20
kDa. Cysteine proteinase inhibitors abolished all gelatinolytic activity at the pH values tested. Such data indicate the presence of cysteine-class proteinases in the ESP of Cyathostominea.
Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic cell transplantation (allo‐HCT) for chronic phase (CP) chronic myeloid ...leukemia (CML) has dramatically decreased. Imatinib was the first TKI introduced to the clinical arena, predominantly utilized in the first line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with either a second or third generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2, or 3 TKI prior to allo‐HCT for CP CML in 904 patients. A total of 323‐, 371‐, and 210 patients had 1, 2, or 3 TKI prior to transplant, respectively; imatinib (n = 778), dasatinib (n = 508), nilotinib (n = 353), bosutinib (n = 12), and ponatinib (n = 44). The majority had imatinib as first TKI (n = 747, 96%). Transplants were performed in CP1, n = 549, CP2, n = 306, and CP3, n = 49. With a median follow‐up of 52 months, 5‐year OS for the entire population was 64.4% (95% CI 60.9–67.9%), PFS 50% (95% CI 46.3–53.7%), RI 28.7% (95% CI 25.4–32.0%), and NRM 21.3% (95% CI 18.3–24.2%). No difference in OS, PFS, RI, or NRM was evident related to the number of TKI prior to allo‐HCT or to the type of TKI (p = ns). Significant factors influencing OS and PFS were > CP1 versus CP1 and Karnofsky performance (KPS) score > 80 versus ≤80, highlighting CP1 patients undergoing allo‐HCT have improved survival compared to >CP1 and the importance of careful allo‐HCT candidate selection.
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