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      Lysosomal storage diseases

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          Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis

          Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases 1–4 . Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism 5 . Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase 1 , which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria–lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria–lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation 6,7 . Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Mitochondria–lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.
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            Delivery technologies for genome editing

            Genome editing has emerged as an attractive approach to therapeutically manipulate gene expression. Here, Anderson and colleagues provide an overview of genome-editing platforms, focusing on the methods and challenges of intracellular biomacromolecule delivery. Preclinical and clinical trials involving genome-editing technologies are also discussed.
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              Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.

              Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease. We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity). Patients were started on 100 mg oral OGT 918 three times daily. Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment. Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.
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                Author and article information

                Journal
                Nature Reviews Disease Primers
                Nat Rev Dis Primers
                Springer Nature America, Inc
                2056-676X
                December 2018
                October 1 2018
                December 2018
                : 4
                : 1
                Article
                10.1038/s41572-018-0025-4
                © 2018

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