G A Grabowski

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

..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...

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

..This study indicates that the multiple cellular functions, i.e., translation control, interleukin-2 enhancer binding, or cell division, of TCP/ILF3 are fulfilled by alternatively spliced isoforms...

..These results indicate that Sp4 and RORalpha play minor and major roles, respectively, in regional expression of the prosaposin locus in the brain, whereas expression in the spinal cord is independent of RORalpha...

..TG and cholesterol levels decreased by approximately 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD...

..The involvement of macrophages throughout the body of lal-/- mice provide evidence for a critical nonappreciated role of LAL in cellular cholesterol and fatty acid metabolism, adipocyte differentiation, and fat mobilization...

..These results indicate that the saposin C-induced conformational change in the enzyme occurs via highly specific, probably multivalent, interactions between acid beta-glucosidase and saposin C...

..TCP80 is likely identical to MPP4 and NF90, but has previously undescribed roles in cellular function...

..Compared to the mouse promoter, the human promoter is missing a Sp1 cluster within a 310-bp upstream segment, and has AP-1, Oct-1 and two RORalpha sites that are protected from DNaseI by selected nuclear extracts...

..These studies demonstrate a relationship between glucosylceramide accumulation and α-synuclein aggregates, and implicate glucosylceramide accumulation as risk factor for the α-synucleinopathies...

..These interactions depend on the tissue-specific repertoire of transcription factors leading to differential expression of this locus...

..The lal-/lal- mice provide a model to determine the role of LAL in lipid metabolism and the pathogenesis of its deficiency states...

..These tissue-, cell-, and developmental stage-specific variations of the gba mRNA level indicate major developmentally regulated changes in the expression pattern of gba in the late gestational period and postnatally...

..The discrete temporal and spatial variations of GAA mRNA during development indicate different physiological roles for this enzyme in various cell types and developmental stages...

..The results suggest that E8SJM leads to essentially a null allele and that the differences in WD and CESD phenotype involve other factors...

..Here, we review the current state of the molecular pathogenesis and provide our perspective of some major issues for continued advances in this prototype lysosomal storage disease...

..Similarity in phenotype between the groups implies that the several genes involved in causing RTS likely have effects through the same pathway...

..An extensive review of the clinical and pathologic involvement by Gaucher disease is available...

..The cytoplasmic protein was not detected in insect cells. These results implicate acid beta-glucosidase coding sequences and a heat labile cytoplasmic protein in modulating the translation of overexpressed mRNA in transgenic cell lines...

..The commonality of these two mutations in the Korean and Chinese (Taiwanese) population indicates the need for more extensive screening for these mutations in the Gaucher populations...

..A negative regulatory element is located between 742 and 310 bp 5' to the transcription start site. These studies provide insight into the regulation of this unique "lysosomal" locus...

..Such membrane interactions and orientations of the saposins determine the proximity of their activation and/or binding sites to lysosomal hydrolases or lipoid substrates...

..These data indicate that the "high' and "low' CYP1A1 inducibility trait, in the population studied, cannot be explained by a difference among these 31 amino acids in exon 9 of the AHR gene...

..Du, H., D. P. Witte, and G. A. Grabowski. Tissue and cellular specific expression of murine lysosomal acid lipase mRNA and protein...

..The spatial organization of expression suggests a role for this locus in the expression of glycosphingolipid-storage diseases...

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

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

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

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

..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...

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

..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...

..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...

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

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..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...

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

..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...

..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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..CONCLUSIONS: Our in vivo and in vitro results suggest that lysosomal enzymes released from macrophages may induce hydrolytic modification of LDL and foam cell formation in the human arterial intima...

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

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

..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...

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

..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...

..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...

..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...

..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...

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

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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...

..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...

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

..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...

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