Competing for the treasure in exceptions

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
American Journal of Hematology (Impact Factor: 3.48). 03/2013; 88(3):163-5. DOI: 10.1002/ajh.23399
Source: PubMed
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    ABSTRACT: Lysosomal storage diseases are inborn errors of metabolism, the hallmark of which is the accumulation, or storage, of macromolecules in the late endocytic system. They are monogenic disorders that occur at a collective frequency of 1 in 5,000 live births and are caused by inherited defects in genes that mainly encode lysosomal proteins, most commonly lysosomal enzymes. A subgroup of these diseases involves the lysosomal storage of glycosphingolipids. Through our understanding of the genetics, biochemistry and, more recently, cellular aspects of sphingolipid storage disorders, we have gained insights into fundamental aspects of cell biology that would otherwise have remained opaque. In addition, study of these disorders has led to significant progress in the development of therapies, several of which are now in routine clinical use. Emerging mechanistic links with more common diseases suggest we need to rethink our current concept of disease boundaries.
    Nature 06/2014; 510(7503):68-75. DOI:10.1038/nature13476 · 42.35 Impact Factor
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    ABSTRACT: Neurodegenerative monogenic diseases often affect tissues and organs beyond the nervous system. An effective treatment would require a systemic approach. The intravenous administration of novel therapies is ideal but is hampered by the inability of such drugs to cross the blood-brain barrier (BBB) and precludes efficacy in the central nervous system. A number of these early lethal intractable diseases also present devastating irreversible pathology at birth or soon after. Therefore, any therapy would ideally be administered during the perinatal period to prevent, stop, or ameliorate disease progression. The concept of perinatal gene therapy has moved a step further toward being a feasible approach to treating such disorders. This has primarily been driven by the recent discoveries that particular serotypes of adeno-associated virus (AAV) gene delivery vectors have the ability to cross the BBB following intravenous administration. Furthermore, safety has been demonstrated after perinatal administration mice and non-human primates. This review focuses on the progress made in using AAV to achieve systemic transduction and what this means for developing perinatal gene therapy for early lethal neurodegenerative diseases.
    Frontiers in Molecular Neuroscience 11/2014; 7:89. DOI:10.3389/fnmol.2014.00089
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    ABSTRACT: Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury.
    Nature medicine 01/2014; DOI:10.1038/nm.3449 · 28.05 Impact Factor