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C Vogler

Publications and source records attributed to C Vogler.

At least 19 recordsLinked to original sources
PubMed2001

Active site mutant transgene confers tolerance to human beta-glucuronidase without affecting the phenotype of MPS VII mice.

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of beta-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gus(mps/mps)) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human beta-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gus(mps/mps)) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gus(mps/mps)) mouse. However, they are now tolerant to immune challenge with human beta-glucuronidase. This "tolerant MPS VII mouse model" should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

Animals↗
PubMed2001

Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors.

Gene therapy using recombinant adeno-associated virus vectors (rAAV) is generally considered safe. During the course of a study designed to determine the long-term efficacy of rAAV-mediated gene therapy initiated in newborn mice with the lysosomal storage disease, mucopolysaccharidosis type VII (MPSVII), a significant incidence of hepatocellular carcinomas and angiosarcomas was discovered. A hepatocellular carcinoma was first detected in a 35-week-old mouse and by 72 weeks of age, three out of five rAAV-treated MPSVII mice had similar lesions. These types of tumors had not been seen previously in long-term studies of MPSVII mice using recombinant enzyme or bone marrow transplantation. In an attempt to ascertain whether mouse strain or GUSB expression confers susceptibility to tumor formation, we histopathologically examined untreated normal mice of the same strain, untreated MPSVII mice, and normal mice overexpressing human GUSB for the presence of tumors and increased hepatocyte replication. The results of these studies do not indicate that MPSVII mice or mice overexpressing human GUSB are susceptible to tumor formation; however, the number of animals examined is too small to draw definitive conclusions. Results from quantitative PCR performed on the tumor samples suggest that the tumors are probably not caused by an insertional mutagenesis event followed by the clonal expansion of a transformed cell. In a separate study, a relatively large group of mice injected with varying doses and types of rAAV vectors had no evidence of hepatic or vascular tumors. Although the mechanism of tumor formation is currently unknown, the tumorigenic potential of rAAV vectors must be rigorously determined in long-term in vivo studies.

Animals↗
PubMed2001

A novel model of murine mucopolysaccharidosis type VII due to an intracisternal a particle element transposition into the beta-glucuronidase gene: clinical and pathologic findings.

We describe the clinical and pathologic findings in a murine model of mucopolysaccharidosis VII (Sly disease) that arose spontaneously in the C3H/HeOuJ mouse strain. Affected gus(mps2J)/gus(mps2J) mice are deficient in beta-glucuronidase because of insertion of an intracisternal A particle element into intron 8 of the gus structural gene. This is the first model of a human lysosomal storage disease caused by an intracisternal A particle element insertion. Mice with the gus(mps2J)/gus(mps2J) genotype have < 1% of normal beta-glucuronidase activity and secondary elevations of other lysosomal enzymes. The phenotype includes shortened life-span, dysmorphic features, and skeletal dysplasia. Lysosomal storage of glycosaminoglycans is widespread and affects the brain, skeleton, eye, ear, heart valves, aorta, and the fixed tissue macrophage system. Thus the phenotypic and pathologic alterations in gus(mps2J)/gus(mps2J) mice are similar to those in patients with mucopolysaccharidosis VII. The finding of antibodies to beta-glucuronidase in some older gus(mps2J)/gus(mps2J) mice suggests the mice produce sufficient enzyme to elicit an immune response. The gus(mps2J)/gus(mps2J) model provides another well-defined genetic system for the study of the pathophysiology of mucopolysaccharidosis and for evaluation of experimental therapies for lysosomal storage diseases. The disease in gus(mps2J)/gus(mps2J) mice is less severe than that seen in the previously characterized B6.C-H2(bm1)/ByBir-gus(mps)/gus(mps) mouse model. Furthermore, unlike gus(mps)/gus(mps) mice, gus(mps2J)/gus(mps2J) mice are fertile and breed to produce litters, all of which are mucopolysaccharidosis VII pups. This feature makes them extremely useful for testing intrauterine therapies.

Animals↗
PubMed2000

Placental pathology for the surgical pathologist.

Pathologic examination of the placenta is of clinical importance in the evaluation of pregnancies with a less than perfect outcome. Morphologic alterations of the placenta can mirror disorders of the fetus and the mother and evaluation of the placenta can identify clinically significant lesions, allow understanding of a child's disability and may have a role in resolving medical-legal disputes. Pathologic findings in the placenta can provide information on the pathogenesis of cerebral palsy, mental retardation, or neurodevelopmental disorders. This review will cover a variety of frequently encountered, clinically important, and morphologically distinct disorders of the placenta. The current understanding of the clinical implications of lesions for the mother, infant, and for future pregnancies will also be considered.

Adult↗
PubMed1999

Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease.

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type VII (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 x 10(6) infectious units of recombinant adeno-associated virus encoding the human beta-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB expression were achieved by 1 week of age in liver, heart, lung, spleen, kidney, brain, and retina. GUSB expression persisted in most organs for the 16-week duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microglia, and meninges of the central nervous system were virtually cleared of disease. In addition, neonatal treatment of MPS VII mice provided access to the central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adeno-associated virus can achieve therapeutically relevant levels of enzyme very early in life and that the rapid growth and differentiation of tissues does not limit long-term expression.

Animals↗
PubMed1999

Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged beta-glucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice.

For many metabolic diseases, early correction of the inherited deficiency is required to prevent long-term sequelae. We examined the ability of adeno-associated virus (AAV) to mediate efficient gene transfer during the neonatal period in mice with the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII). Quadriceps of newborn MPS VII mice were injected with an AAV vector containing human beta-glucuronidase (GUSB) cDNA. High-level intramuscular GUSB expression was seen as early as 2 weeks of age, and persisted for at least 16 weeks with no reduction in activity. In addition, GUSB activity was detected in both liver and spleen at later time points. The level of GUSB activity resulted in a significant reduction in lysosomal storage in the liver and a minimal reduction in the spleen at 16 weeks. However, the temporal and spatial pattern of hepatic GUSB activity, coupled with the presence of GUSB cDNA in liver sections, suggests that hematogenous dissemination of virus at the time of injection led to gene transfer to hepatic cells. These results demonstrate that AAV vectors can successfully infect neonatal muscle and persist through the rapid growth phase following birth. However, GUSB secretion from an intramuscular source is inefficient, limiting the therapeutic efficacy of this approach.

Age Factors↗
PubMed1999

Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy.

We have previously shown that mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly injections of recombinant beta-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single beta-glucuronidase injection at 5 wk of age did not correct neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to beta-glucuronidase therapy and determine the effect of enzyme on other tissues by comparing the histology of mice begun on therapy at various times after birth. MPS VII mice received injections on the day of birth and then weekly for 5 wk with 16,000U/g beta-glucuronidase had reduced lysosomal storage in brain. The same therapy begun on d 14 of life or thereafter failed to correct neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibility to enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and retinal pigment epithelial storage reduction depended on enzyme dose rather than age at initiation of therapy. Fixed tissue macrophage storage was reduced in all treated MPS VII mice, even those receiving a single dose. These observations indicate that fixed tissue macrophages in MPS VII mice remain sensitive to enzyme replacement therapy well into adulthood although neurons are responsive or accessible to enzyme therapy early in life. Because early initiation of enzyme replacement is important to achieve a central nervous system response, these studies emphasize the importance of newborn screening for lysosomal storage diseases so that early treatment can maximize the likelihood of a favorable therapeutic response.

Anaphylaxis↗
PubMed1999

Inhibitory and excitatory responses of olfactory receptor neurons of xenopus laevis tadpoles to stimulation with amino acids

Recordings were made from olfactory receptor neurons of Xenopus laevis tadpoles using the patch-clamp technique to investigate the responses of these cells to odorants. Four amino acids (glutamate, methionine, arginine and alanine) both individually and as a mixture were used as stimuli. Of the 156 olfactory neurons tested, 43 showed a response to at least one of the stimuli. Of the cells tested, 19 % responded to glutamate, 16 % to methionine, 12 % to arginine and 10 % to alanine. Each amino acid was able to induce both excitatory and inhibitory responses, although these occurred in different cells. Each amino acid produced approximately equal numbers of inhibitory and excitatory responses. Inhibitory responses could best be observed in the perforated-patch configuration using gramicidin as an ionophore and a recording configuration that is a current-clamp for fast signals and a voltage-clamp for slow signals. The diversity of the odorant responses, in particular the existence of excitatory and inhibitory responses, is not consistent with a single transduction pathway in olfactory neurons of Xenopus laevis tadpoles.

Journal Article↗
PubMed1999

Clinical and pathologic findings in two new allelic murine models of polycystic kidney disease.

Patients with inherited cystic kidney diseases have progressive cystic dilation of nephrons with concomitant loss of functional renal parenchyma and renal failure. Animal models of inherited cystic kidney disease are useful for study of the pathogenesis and molecular basis of cystic renal diseases. This article describes the clinical and pathologic features in two spontaneously occurring murine models of inherited polycystic kidney disease due to independent allelic mutations on mouse chromosome 8. The mutations, designated kat and kat2J, affect a chromosomal segment homologous to a region of human chromosome 4q35; the altered gene has not yet been identified. An allelism test showed that the mutations are at the same locus. The phenotype, inherited as an autosomal recessive, is more severe in kat2J/kat2J mice. Their kidneys are morphologically normal at birth, but by 3 mo of age, cysts affect all levels of the nephron. Adult males have testicular hypoplasia and they are sterile. A few of the oldest kat2J/kat2J mice have focal portal bile duct proliferation and dilation. kat2J/kat2J mice develop anemia and uremia and die before 1 yr of age. In kat/kat mice, the renal cystic disease progresses more slowly but is morphologically similar to that of kat2J/kat2J mice. The progressive cystic transformation of the kidneys in these allelic murine models resembles that seen in humans with autosomal dominant polycystic kidney disease.

Age Factors↗
PubMed1998

Murine mucopolysaccharidosis type VII: the impact of therapies on the clinical course and pathology in a murine model of lysosomal storage disease.

Murine mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a recessively inherited deficiency of the lysosomal enzyme beta-glucuronidase. Affected mice have clinical, biochemical and pathological findings similar to those seen in humans with MPS VII (Sly syndrome), including growth retardation, facial dysmorphism, deafness, behavioural deficits and widespread glycosaminoglycan storage in lysosomes in the viscera, skeleton and brain. This mouse model is a useful tool for the evaluation of the effectiveness and experimental therapies for the MPS disorders. Syngeneic bone marrow transplantation performed in newborn MPS VII animals--before clinical evidence of disease is pronounced--prolongs life, improves hearing and bone growth, and prevents lysosomal storage in many sites, but does not correct the central nervous system disease. Enzyme therapy with beta-glucuronidase from the first days of life does reduce lysosomal storage in the brain in murine MPS VII. The enzyme-replaced mice also have reduced visceral lysosomal storage, impressive normalization of their phenotype and an improved life span. The effectiveness of gene therapy for the treatment of lysosomal storage disease has also been tested using the MPS VII model. When transplanted into MPS VII mice, syngeneic haematopoietic stem cells or mouse skin fibroblasts infected with retrovirus expressing beta-glucuronidase decreased storage, but only in the liver and spleen. Injection of an adenovirus vector expressing beta-glucuronidase into the vitreous of the MPS VII mice reduced storage in the retinal pigment epithelium and corneal endothelium. Intravenous administration of the adenovirus vector transduced with the beta-glucuronidase gene reduced liver and spleen storage and, when instilled into the cerebral ventricles, this viral vector caused beta-glucuronidase production in epithelial cells lining the ventricles. Recently, retroviral vector-corrected MPS VII fibroblasts secreting high levels of beta-glucuronidase were engrafted directly into the brains of adult MPS VII mice with resultant reduction in storage in neurons and glia adjacent to the grafts. Future efforts aimed at prolonging expression of the beta-glucuronidase gene by viral vectors and more precisely directing the therapeutic effect to the skeleton and brain will be important in optimizing treatments for murine MPS VII and extending the results of such therapies to humans with MPS.

Animals↗
PubMed1997

Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.

We demonstrated previously that short term administration of recombinant beta-glucuronidase to newborn mice with mucopolysaccharidosis type VII reduced lysosomal storage in many tissues. Lysosomal storage accumulated gradually after cessation of enzyme replacement therapy. Mice alive at 1 yr of age had decreased bone deformities and less lysosomal storage in cortical neurons. Here we compare the effects of long term enzyme replacement initiated either at birth or at 6 wk of age, and of enzyme administration initiated at birth followed by syngeneic bone marrow transplantation (BMT) at 5 wk of age. Several mice from each treatment group lived to at least 1 yr of age. Liver and spleen samples had beta-glucuronidase levels ranging from 2.4 to 19.8% of normal and showed a parallel decrease in lysosomal storage. The combination of enzyme replacement therapy followed by BMT reduced lysosomal distension in meninges, corneal fibroblasts, and bone when compared with treatment with enzyme alone. Mice treated at birth had less lysosomal storage in some neurons of the brain and the skeletal dysplasia was less severe when compared to mice whose treatment was delayed until 6 wk of age. We conclude that both enzyme replacement alone and early enzyme replacement followed by BMT have long term positive effects on murine mucopolysaccharidosis type VII. In addition, treatment started at birth is far more effective than treatment initiated in young adults.

Animals↗
PubMed1997

Adenovirus-mediated gene transfer and expression of human beta-glucuronidase gene in the liver, spleen, and central nervous system in mucopolysaccharidosis type VII mice.

Mucopolysaccharidosis type VII (Sly syndrome) is a lysosomal storage disease caused by inherited deficiency of the lysosomal enzyme beta-glucuronidase. A murine model of this disorder has been well characterized and used to study a number of forms of experimental therapies, including gene therapy. We produced recombinant adenovirus that expresses human beta-glucuronidase and administered this recombinant adenovirus to beta-glucuronidase-deficient mice intravenously. The beta-glucuronidase activities in liver and spleen were elevated to 40% and 20%, respectively, of the heterozygote enzymatic level at day 16. Expression persisted for at least 35 days. Pathological abnormalities of these tissues were also improved, and the elevated levels of urinary glycosaminoglycans were reduced in treated mice. However, the beta-glucuronidase activity in kidney and brain was not significantly increased. After administration of the recombinant adenovirus directly into the lateral ventricles of mutant mice, the beta-glucuronidase activity in crude brain homogenates increased to 30% of heterozygote activity. Histochemical demonstration of beta-glucuronidase activity in brain revealed that the enzymatic activity was mainly in ependymal cells and choroid. However, in some regions, the adenovirus-mediated gene expression was also evident in brain parenchyma associated with vessels and in the meninges. These results suggest that adenovirus-mediated gene delivery might improve the central nervous system pathology of mucopolysaccharidosis in addition to correcting visceral pathology.

Adenoviridae↗
PubMed1997

Gene therapy for murine mucopolysaccharidosis type VII.

Mucopolysaccharidosis type VII (MPS VII) is caused by a deficiency in the lysosomal enzyme beta-glucuronidase resulting in the accumulation of undegraded glycosaminoglycans in many tissues. A murine model of MPS VII shares many of the clinical, biochemical and histopathological features of human MPS VII and has provided an opportunity to study novel therapeutic approaches in a system with a uniform genetic background. Retroviral mediated gene therapy directed to the hematopoietic system or to artificial neo-organs resulted in low levels of enzyme in several tissues and reduced lysosomal storage in the liver and spleen. Partial correction of the disease in the eye was observed following an intravitreal injection of recombinant adenovirus. Neither retroviral nor adenoviral mediated gene transfer techniques resulted in a systemic reduction of lysosomal storage. Here we discuss several novel gene transfer approaches designed to increase the systemic levels of beta-glucuronidase in the MPS VII mouse.

Adenoviridae↗
PubMed1996

Neuropathology of murine mucopolysaccharidosis type VII.

We describe the neuropathology in mucopolysaccharidosis type VII (MPS VII) mice with a recessively inherited deficiency of the lysosomal enzyme beta-glucuronidase. Affected animals have a shortened life span, are dysmorphic, dwarfed and have clinical evidence of behavioral and memory deficiencies. Widespread lysosomal distention with glycosaminoglycan accumulation affects most viscera. In the central nervous system there is progressive accumulation of lysosomal storage in neurons, glia and mesenchymal tissue. The morphological character and the amount of lysosomal storage varies among neuronal groups. In the hippocampus, regional variation in the abundance of lysosomal storage in the MPS VII mice correlates with regional variation in the amount of beta-glucuronidase activity in normal mice. The MPS VII mouse provides a well-defined genetic system for the analysis of the neuropathology of MPS VII and is an attractive model on which to test the effects of potential therapies for lysosomal storage disease on the central nervous system.

Animals↗
PubMed1996

The inflammatory response in pediatric biliary disease: macrophage phenotype and distribution.

PURPOSE: Extrahepatic biliary obstruction in infants and children leads to ductal hyperplasia and portal fibrosis. Inflammatory mediators responsible for increased cellular proliferation and matrix deposition are hypothesized to result from the intrahepatic recruitment and activation of lymphocytes and macrophages (M phi). The authors previously showed components of this mechanism in studies that demonstrated increased adhesion molecule expression in biliary atresia, as well as evidence of altered hepatic M phi function during the course of experimental cholestatic liver injury. Therefore they sought determine the expression of macrophage receptor markers CD68 and CD14 in pediatric biliary disease. METHODS: Sixteen liver specimens were snap-frozen and cryosectioned onto polylysine-coated slides. Sections were stained with murine monoclonal antibodies to CD68 (resident M phi) and CD14 (monocyte-M phi lipopolysaccharide [LPS] receptor) glycoproteins. The sections were analyzed using a semiquantitative scale of proliferation and were position-graded from 0 to 3 (maximal). RESULTS: Blinded analysis showed that marked proliferation of CD68-positive cells occurred in five of the six patients with biliary atresia (BA) and in one patient who had severe cholestasis. Normal perisinusoidal liver M phi were found in specimens from patients with hepatitis (2), choledochal cyst (1), and congenital hepatic fibrosis (1). Similarly, expression of CD14 periportal M phi was found only in patients with BA or cholestasis (1.9 +/- 0.3 [mean +/- SEM]) and was absent in other diseases. Strong sinusoidal expression of CD14 was evident in all patients who had extrahepatic biliary obstruction. An early biopsy specimen from a premature infant with BA did not show cholestasis, fibrosis, CD68 Mø proliferation, or CD14 expression; however, another biopsy specimen, obtained further in the course of jaundice showed the progressive development of all features. CONCLUSION: These findings suggest proliferation of resident M phi in association with cholestasis. The presence of the LPS receptor on periportal cells during cholestatic liver injury points to a potential source of cytokines responsible for the inflammatory reaction of biliary atresia.

Antigens, CD↗
PubMed1996

Enzyme replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis type VII: impact of therapy during the first six weeks of life on subsequent lysosomal storage, growth, and survival.

Treatment of mucopolysaccharidosis type VII (MPS VII) mice with recombinant mouse beta-glucuronidase injections has been shown to deliver enzyme to most tissues and to reduce lysosomal storage during the first 6 wk of life. Here we determine the effect of enzyme therapy limited to the first 6 wk of life on survival and growth and follow the subsequent accumulation of lysosomal storage after beta-glucuronidase treatment is discontinued. MPS VII mice received 28,000 U of beta-glucuronidase i.v. at weekly intervals from birth to 6 wk of life and were killed at intervals up to 1 y after the last injection. By 29 d after the last enzyme injection, lysosomal storage in bone was no different in amount than that seen in untreated MPS VII mice. By 85 d, the fixed tissue macrophage system, meninges, and brain glia had also accumulated storage comparable to that seen in untreated controls. One year after treatment, lysosomal storage was similar to that of untreated MPS VII mice in all sites except cortical neurons, where there was still a slight reduction. All treated mice that were not killed earlier, lived longer, were larger, and had milder facial and skeletal deformities than untreated MPS VII mice. These data show that enzyme replacement therapy in MPS VII mice during the first 6 wk of life improve survival and growth. After treatment is discontinued, storage accumulates slowly in the brain and more rapidly in the fixed tissue macrophage system. Whether therapy continued later in life can further improve survival and growth remains to be established.

Animals↗