Gregory Grabowski

..Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice...

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..Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies...

..The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients...

..This approach in Gaucher disease provided a prototype for the basic and clinical sciences, and the economic foundation for other ultra-orphan diseases...

..To determine whether enzyme therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients...

..The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure...

..These storage diseases provide the basis for continued development of gene therapy...

..Similar results are being obtained in several other lysosomal storage diseases. Evolving gene and chaperone approaches provide alternative treatment strategies...

..These results support the view that saposin C has multiple roles in glycosphingolipid (GSL) catabolism as well as a prominent function in CNS and axonal integrity independent of its role as an optimizer/stabilizer of GCase...

..These models mimic a more severe Gaucher disease phenotype and could be useful for therapeutic intervention studies...

..These studies may yield a new therapeutic approach for neuron protection, preservation, and regeneration...

..B-/- provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis...

..The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement...

..Alendronate is a useful adjunctive therapy in combination with enzyme replacement therapy (ERT) for the treatment of GD-related osteopenia in adults, but it cannot be expected to improve focal lesions...

..These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses...

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..This CD null mouse model provides a tool to explore the in vivo functional interactions of saposins in GSL metabolism and lysosomal storage diseases, and prosaposin's physiological effects...

..These studies also show in vivo localization of the GCase activation region to the carboxy terminal half of saposin C and the lack of a significant gross trophic effect of saposin C on CNS organization in vivo...

..These GCase-deficient mice provide tools for gaining insight into the pathophysiology of Gaucher disease and developing improved therapies...

..The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions...

..Additional regulatory elements outside the 5' region of the 2400 bp promoter fragment appear to be essential for the physiological control of the prosaposin locus...

..These results also show that the enzymatic activation domain is located at carboxyl-terminal half of saposin C and functions only in the context of the general saposin structure...

..This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo...

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..g. Val --> Leu). These results provide initial studies for the engineering of variant GCases and, potentially, molecular chaperones for therapeutic use...

..Designation of genotype associations with specific phenotypes must be assessed with this perspective...

..These developments are novel, clinically important, advancements for patients with other lysosomal storage diseases and genetic diseases...

..The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression...

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..This study provides insight into the function of these residues in acid beta-glucosidase active site function...

..These complications are unique, indicating poorly accessible, differentially responsive compartments in patients with Gaucher's disease who are receiving enzyme therapy...

..These studies provide the basis for the use of gene therapy, in the form of gene transfer via intravenously administered adenovirus, to correct deficiency states, such as WD and CESD, and histopathology of a variety of tissues...

..CONCLUSIONS: These results support the potential utility of lysosomal acid lipase supplementation for the treatment of atherosclerosis, a leading cause of mortality and morbidity in Westernized nations...

..Thus, diminished in vivo GCase activity would be greater than expected only from the lack of GCase activation by saposin C. These results indicate a new property for saposin C, an anti-proteolytic protective function toward GCase...

..CONCLUSION: A thorough approach to baseline assessment will improve the understanding of childhood Gaucher disease, optimizing management to minimize impairment of growth and development and prevent irreversible symptoms...

..Major clinical advances in Gaucher disease focus on detection, prediction and treatment of variant phenotypes...

..These studies demonstrate the feasibility of using plant-expressed, recombinant hLAL for the enzyme therapy of human WD/CESD with general implications for other lysosomal storage diseases...

..The principles, progress, and practice in these diseases provide prototypes for expansion of enzyme therapy to a growing set of these diseases...

..These are the focus of this review...

..These findings indicate potential broader impacts of the TCP/PKC system on expression of this and other genes of therapeutic interest...

..This study provides an approach to investigate the structure-function aspects of Sap C interaction with phospholipid membranes, with insights into the mechanism(s) of Sap C-membrane interaction...

..Addition of selected saposin C peptides prior to intact saposin C in reaction mixtures abolished the liposomal fusion. These results indicated that saposin-membrane and saposin-saposin interactions are needed for the fusion process...

..The findings also emphasize the need for caution in making generalizations about Gaucher disease across demographic groups...

..These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher disease...

..CONCLUSION: Through comprehensive and serial monitoring, ultimately, a therapeutic dose of enzyme therapy that achieves sustained benefits can be found for each child with non-neuronpathic Gaucher disease...

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..LTPs constitute a previously unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens...

..Here we establish goals of treatment in Gaucher disease and propose a comprehensive schedule of monitoring of all relevant aspects to confirm the achievement, maintenance, and continuity of the therapeutic response...

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..Here, the clinical and molecular findings of the subacute neuronopathic variant are delineated among ethnic Poles...

..This approach offers the potential for more complete therapy, including the CNS, as well as less expensive and more convenient therapy for this disease as prototype for this class of disorders. ..

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..These studies have implications for GSL metabolism, and lysosomal storage disease phenotypic expression and therapy. ..

..These studies should provide insights into the pathophysiology and therapy of GD, and to over 20 glycolipid storage diseases that depend on the GCS synthetic and GCase degradative pathwavs. ..

..These studies have implications for GSL metabolism, and lysosomal storage disease phenotypic expression and therapy. ..

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..This approach offers the potential for more complete therapy, including the CNS, as well as less expensive and more convenient therapy for this disease as prototype for this class of disorders. ..

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..These studies have implications for GSL metabolism, and lysosomal storage disease phenotypic expression and therapy. ..

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..The results of these experiments have major import for understanding CNS development, nerve regeneration, GSL metabolism and the pathophysiology of GSL inborn errors of metabolism. ..

..The results of these investigations should provide a deeper understanding of beta-GIc's function and the pathophysiology of GD as a basis for improved therapies for this and other inborn errors of metabolism. ..

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