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PubMed1998

Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin.

BACKGROUND & AIMS: Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Epidemiological and experimental data indicate that regular use of aspirin reduces colon cancer risk. This study was designed to determine if aspirin would significantly inhibit gastrointestinal tumor formation in a mouse model of familial adenomatous polyposis. METHODS: Six-week-old male and female C57BL/6J +/+ (control) and C57BL/6J ApcMin/+ (Min) mice were fed either a control AIN-76A diet or one supplemented with 250 or 500 parts per million (ppm) aspirin (n = 6 per group) for 7 weeks. RESULTS: All of the Min mice, but no control mice, developed gastrointestinal tumors. Aspirin significantly reduced tumor multiplicity (number of tumors per mouse) in the small intestine, but not the colon, from an average of 35.8 tumors per mouse (control diet) to 16 and 18.5 tumors per mouse with 250 and 500 ppm aspirin, respectively. Total tumor load (sum of tumor diameters per mouse) was also significantly reduced, from 93.2 mm in total diameter to 40. 4 and 45.0 mm with 250 and 500 ppm aspirin, respectively. Results were not significantly different because of sex or aspirin dose. CONCLUSIONS: High doses of aspirin are effective chemopreventive agents in a mouse model of spontaneous intestinal tumor formation.

Adenoma↗
PubMed1998

Selective loss of alpha motoneurons innervating the medial gastrocnemius muscle in a mouse model of amyotrophic lateral sclerosis.

Mutations in the superoxide dismutase gene 1 (SOD-1) are found in patients with familial amyotrophic lateral sclerosis (FALS). Overexpression of a mutated human SOD-1 gene in mice results in neurodegenerative disease as result of motoneuron loss in lumbar spinal cord (10). Using this mouse model of FALS, we have established a quantitative assay utilizing the retrograde tracer Fluorogold (FG) to determine the number of motoneurons innervating one skeletal muscle in mice with ongoing disease. In adult wild-type mice, the number of alpha motoneurons retrogradely labeled by an injection of FG into medial gastrocnemius muscle is 50 +/- 7 and this number remains constant from 7 to 18 weeks of age. In mutant mice, the number of alpha motoneurons retrogradely labeled by FG is the same as in wild-type mice at 7 and 9 weeks, but then declines to 36% of that in normal mice at 18 weeks. This decline also correlates positively to severity of motor impairments in these mice as assessed by the hindlimb splay test. In contrast, the number of FG-labeled gamma motoneurons remains relatively unchanged in both wild-type and mutant mice up to 18 weeks. At 18 weeks of age, this apparent alpha motoneuron denervation is paralleled by an average of 55% reduction of MG-muscle mass and 40% weaker performance in the hindlimb splay test. These data suggest that alpha motoneurons are the most vulnerable neuronal subtype in this mouse model of ALS and it is primarily their loss that leads to functional motor deficits. This quantitative bioassay also will be valuable for evaluating novel therapeutics for ALS.

Aging↗
PubMed1995

Analyses of homologous rotavirus infection in the mouse model.

The group A rotaviruses are significant human and veterinary pathogens in terms of morbidity, mortality, and economic loss. Despite its importance, an effective vaccine remains elusive due at least in part to our incomplete understanding of rotavirus immunity and protection. Both large and small animal model systems have been established to address these issues. One significant drawback of these models is the lack of well-characterized wild-type homologous viruses and their cell culture-adapted variants. We have characterized four strains of murine rotaviruses, EC, EHP, EL, and EW, in the infant and adult mouse model using wild-type isolates and cell culture-adapted variants of each strain. Wild-type murine rotaviruses appear to be equally infectious in infant and adult mice in terms of the intensity and duration of virus shedding following primary infection. Spread of infection to naive cagemates is seen in both age groups. Clearance of shedding following primary infection appears to correlate with the development of virus-specific intestinal IgA. Protective immunity is developed in both infant and adult mice following oral infection as demonstrated by a lack of shedding after subsequent wild-type virus challenge. Cell culture-adapted murine rotaviruses appear to be highly attenuated when administered to naive animals and do not spread efficiently to nonimmune cagemates. The availability of these wild-type and cell culture-adapted virus preparations should allow a more systematic evaluation of rotavirus infection and immunity. Furthermore, future vaccine strategies can be evaluated in the mouse model using several fully virulent homologous viruses for challenge.

Animals↗
PubMed1997

Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.

Administration, Oral↗
PubMed1997

Toward a transgenic mouse model of remyelination.

The molecular mechanisms necessary for remyelination by oligodendrocytes remain unexplored. We previously characterized a myelin basic protein promoter-lacZ (MBP-lacZ) transgene whose expression is regulated uniquely during development, and also in pathological situations, suggesting that it may be a useful reporter of molecular mechanisms during remyelination. As a first step toward creating a transgenic mouse model of remyelination, we cultured oligodendrocytes from these transgenic mice and showed that expression of MBP-lacZ appeared in parallel with a marker of oligodendrocyte maturation, galactocerebroside (GC). In addition, basic fibroblast growth factor blocked the expression of both MBP-lacZ and GC in these cells. Therefore, expression of MBP-lacZ reflects not only the developmental stage of oligodendrocytes, but also extrinsic influences on oligodendrocytes. These data suggest that MBP-lacZ may be a useful marker in transgenic mouse models of remyelination.

Animals↗
PubMed1998

A mouse model to test the in vivo efficacy of chemical chaperones.

In vitro studies in transfected cells have indicated that chemical chaperones including glycerol (0.5-1.2 M) and trimethylamine oxide (TMAO, 50-100 mM) can correct defective trafficking of some proteins, including deltaF508 CFTR in cystic fibrosis and AQP2 mutants in nephrogenic diabetes insipidus. To develop a mouse model to test the efficacy of chemical chaperones in vivo, glycerol and TMAO were administered by intraperitoneal (i.p.), subcutaneous (s.c.), and oral routes. Glycerol and TMAO assays that utilized 1-5 microL of tail vein blood were developed. Administration by the i.p. and s.c. routes gave maximum serum glycerol concentrations of approximately 100 mM, levels that were well below the effective in vitro concentrations. Single i.p. or s.c. doses of TMAO (7 g/kg, 8% solution in water) resulted in serum [TMAO] greater than 50 mM, with a long half-life (t1/2 approximately equal to 18-21 h). Sustained high serum and tissue [TMAO] > 52 mM for 3 days was achieved by s.c. administration of TMAO (7 g/kg) in water every 8 h. Although approximately 50% of the mice died with this multiple-dose regimen, the remaining mice had nearly normal liver, renal, and pancreatic function. A lower dose of TMAO (5 g/kg) given by the s.c. route every 8 h resulted in serum [TMAO] concentration of 22 mM, a level that was well tolerated by all mice for 72 h. These mice also had high [TMAO] in urine, 400 mM. These results demonstrate that potentially therapeutic concentrations of TMAO can be sustained in mice in vivo, permitting the testing of chemical chaperones in transgenic mouse models of diseases caused by defective protein trafficking.

Animals↗
PubMed2026

Motor coordination and behavioural deficits in a mouse model of KMT2B-related dystonia.

INTRODUCTION: Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. METHODS: We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioural traits, motor coordination, sensorimotor gating, social behaviour and metabolic parameters, combined with striatal RNA sequencing. RESULTS: Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and haematological measures were largely unaffected. CONCLUSION: Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.

Dystonia↗
PubMed1997

Androgen stimulation of lacrimal gland function in mouse models of Sjögren's syndrome.

Sjögren's syndrome, an autoimmune disease that occurs primarily in women, causes extensive inflammation and significant dysfunction in the lacrimal gland, and is one of the leading causes of dry eye syndromes throughout the world. Recently, our research has shown that androgen treatment causes a significant suppression of the immunopathological lesions in lacrimal tissues of female mouse models (MRL/Mp-lpr/lpr [MRL/lpr] and NZB/NZW F1 [F1]) of Sjögren's syndrome. To extend these findings, the objective of the present study was to determine whether this androgen-induced anti-inflammatory action may be paralleled by an increase in the functional activity of lacrimal glands in these autoimmune mice. Towards this end, we measured the tear levels of immunoglobulin A (IgA), which originates from lacrimal tissue and whose concentration is known to be diminished in mucosal sites in Sjögren's syndrome. For comparative purposes, we also evaluated whether the administration of other steroid hormones or immunosuppressive agents might duplicate possible androgen effects on the secretory function of lacrimal tissue. Female MRL/lpr and F1, as well as non-autoimmune BALB/c, mice were treated with vehicle, steroids or immunosuppressive compounds for 17 to 54 days after the onset of disease. Lacrimal glands, tears and sera were collected immediately before (pretreatment), or after, therapy and processed for the analysis of either tear IgA (enzyme-linked immunosorbent assay; ELISA) and protein content or the magnitude of lymphocyte infiltration (computer-assisted image analysis). Our findings demonstrated that testosterone treatment stimulated a significant increase in the concentration and total amount of tear IgA, as well as tear protein, compared to levels in pretreatment or placebo controls. This hormone action was reproduced by exposure to a diverse array of "anabolic" and "androgenic" androgen analogues, but not by treatment with estradiol, danazol, cyclosporine A, dexamethasone or cyclophosphamide. In contrast, only dexamethasone increased serum IgA concentrations. Of particular interest is the fact that the androgen control of IgA output by the lacrimal gland appeared to be independent of this steroid's suppression of lymphocyte infiltration in lacrimal tissue. Overall, these results show that androgen therapy enhances the functional activity of the lacrimal gland in mouse models of Sjögren's syndrome.

Androgens↗
PubMed1998

Mouse models of myelin diseases.

Dys- and demyelination are the common endpoints of several inherited diseases of glial cells, which elaborate myelin and which maintain the myelin sheath very much like an "external" cellular organelle. Whereas some of the genes that are affected by mutations appear to be glial-specific, other genes are expressed in many cell types but their defect is restricted to oligodendrocytes or Schwann cells. Many of the disease genes and their encoded proteins have been studied with the help of mouse models, and a number of different molecular pathomechanisms have emerged which have been summarized in Figure 8. Some of the new concepts in the field, which have been addressed in this review, have only emerged because similar pathomechanisms were discovered for different myelin proteins. Mouse models have clearly helped to address both, the molecular pathology of myelin diseases and the normal function of myelin genes, but as discussed in this review, these questions turned out to be very different. Despite the progress in understanding the role of the abundant myelin proteins, there also remain a number of open questions that concern, among other things, the initial axon-glia recognition, the assembly process of the myelin sheath, and the long-term interaction of axons with their myelinating glia. Finally, animal models of human neurological diseases should not be restricted to the study of pathology, but they should also contribute to the development of experimental treatments. It is encouraging that a few attempts have been made.

Animals↗
PubMed1998

Development of a mouse model system, coding assignments and identification of the genome segments controlling virulence of African horse sickness virus serotypes 3 and 8.

Attenuated (att) and wild type (wt) strains of the nine AHSV serotypes were evaluated for virulence in adult Balb C mice. Although most were avirulent in this system, isolates of AHSV 1att, 3wt, 3att, 4wt, 5att, 7att and 8att caused some mortality when administered via an intranasal route. After plaque cloning, only the attenuated vaccine strain of AHSV 7att caused any mortality via an intravenous route. AHSV 3att and AHSV 8wt were virulent (V) and avirulent (AV) (respectively) in the mouse model and were selected as parental strains for production of genome segment reassortants. These progeny virus strains were plaque cloned, then characterised to identify the genome segments that influence virulence of AHSV in the mouse model. Three virulence phenotypes were observed: fully virulent (V); fully avirulent (A); and a novel intermediate virulence (N) not expressed by either parental strain. Genome segment 2 (encoding outer capsid protein VP2) from the avirulent parent appeared to have a controlling influence in production of the A phenotype. Reassortants with the V phenotype all contained segment 2 from the virulent parent, however in each case they also contained genome segments 5 and 10, also from AHSV 3 (V). Genome segments 5 and 10 encode the smaller outer capsid protein VP5 and the non structural proteins NS3/NS3a, respectively. A combination of genome segments 2, 5 and 6 from the avirulent parent and segment 10 from the virulent parent were found in each of the virus strains with the N phenotype. However, comparison of two reassortants (A79 and A790), which differ only in a single segment, showed that replacement of genome segment 10 from the avirulent parent with that from the virulent parent, conferred the N phenotype on A790.

African Horse Sickness↗
PubMed1998

Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems.

In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence-activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)-2/15 receptor beta (CD122) chain and common gamma (gamma c) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with gamma c. Recently developed IL-15 and IL-15 receptor alpha knockout mice have pinpointed IL-15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK-cell development as well as minor roles for stem cell factor and IL-7 in expanding NK-cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.

Animals↗
PubMed1994

Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited human diseases in which photoreceptor degeneration leads to visual loss and eventually to blindness. Although mutations in the rhodopsin, peripherin, and cGMP phosphodiesterase genes have been identified in some forms of RP, it remains to be determined whether these mutations lead to photoreceptor cell death through necrotic or apoptotic mechanisms. In this paper, we report a test of the hypothesis that photoreceptor cell death occurs by an apoptotic mechanism in three mouse models of RP: retinal degeneration slow (rds) caused by a peripherin mutation, retinal degeneration (rd) caused by a defect in cGMP phosphodiesterase, and transgenic mice carrying a rhodopsin Q344ter mutation responsible for autosomal dominant RP. Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling. Both methods showed extensive apoptosis of photoreceptors in all three mouse models of retinal degeneration. We also show that apoptotic death occurs in the retina during normal development, suggesting that different mechanisms can cause photoreceptor death by activating an intrinsic death program in these cells. These findings raise the possibility that retinal degenerations may be slowed by interfering with the apoptotic mechanism itself.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Loss of myelinated axons is specific to the central nervous system in a mouse model of the fetal alcohol syndrome.

We have previously developed a mouse model of the fetal alcohol syndrome, the outcome of which is a late loss of myelinated axons in the optic nerve of offspring of alcohol-treated mice between 9 and 15 wk of age. We have extended this study to investigate whether this axon loss is stable and specific to the central nervous system. Pregnant female (C57BL/6/Wlds x CBA) F1 mice were injected intraperitoneally with a single dose of a 25% solution of ethanol (v:w), on d 12 of gestation. Control animals were given a similar volume of saline at the same time. Litters were taken at 12 (n = 18) and 23 (n = 26) wk of age. Optic nerves only from 12-wk-old, and optic, tibial and saphenous nerves from 23-wk-old mice were removed. A systematic, random sampling method was used to estimate the cross-sectional area of whole nerves from semi thin sections, and the numbers and diameters of myelinated axons from ultrathin sections. There were no differences for the optic nerves of 12-wk-old alcohol-treated and control animals. Optic nerves from the alcohol-treated group at 23 wk had smaller cross-sectional areas and approximately 17% fewer myelinated axons than control nerves. These results confirm that axon loss occurs between 12 and 15 wk, and demonstrate that there is no additional loss of myelinated axons between 15 and 23 wk. In contrast, there were no significant differences in cross-sectional area, number of myelinated axons or axon calibre spectra for the tibial and saphenous nerves between the alcohol-treated and control groups. There was thus no evidence of a peripheral neuropathy as has been observed in chronic alcoholic subjects. In this 'binge' model of the fetal alcohol syndrome, a carefully timed dose of alcohol is administered during pregnancy to coincide with a critical period of development of the visual system. The result is a teratogenic effect which is specific to the central nervous system, stable and reproducible, with no obvious effect on the peripheral nervous system.

Animals↗
PubMed1985

Anticonvulsant action of GABA agonists and prodrugs on minor and major seizures in epileptic gerbils. Comparison with mouse models of seizure states.

The anticonvulsant efficacy of the GABAmimetic drugs cetyl GABA, progabide and THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) was studied against minor (myoclonic) and major (generalized tonic-clonic) seizures in gerbils as well as against maximal electroshock and s.c. pentylenetetrazol-induced seizures in mice. Seizures in gerbils were evoked by a blast of compressed air. THIP and progabide were about equally active to protect gerbils against minor and major seizures. ED 50s for THIP were 0.98 and 1.3 mg/kg and for progabide 58 and 50 mg/kg i.p., respectively. Cetyl GABA failed to show a linear dose-response against minor seizures but was quite potent against major ones (ED 50 4.4 mg/kg). All three GABAmimetics were inactive in the mouse models of seizure states except a weak effect of progabide against maximal electroshock seizures. The data show that seizure-prone gerbils with different seizure types differ strikingly in sensitivity to GABAmimetic drugs from traditional mouse models for anticonvulsant drug evaluation.

Animals↗
PubMed1990

The relationship of excess copper accumulation by fibroblasts from the brindled mouse model of Menkes disease to the primary defect.

Fibroblasts from the brindled mouse model of Menkes disease are known to accumulate excess copper. Most of the copper in the cytosol of these fibroblasts is bound to metallothionein (MT), which is elevated in Menkes or brindled mouse fibroblasts. Copper accumulation by normal fibroblasts containing excess MT was examined to determine if the excess copper accumulation phenotype was secondary to excess MT or associated with the primary defect in fibroblasts from the brindled mice. MT was induced in normal fibroblasts by copper, zinc or dexamethasone to levels comparable with those in brindled mice fibroblasts, as determined by radioimmunoassays. Normal fibroblasts containing excess MT accumulate copper normally, i.e. they do not exhibit the excess copper accumulation phenotype. Consistent with this result, copper efflux from normal fibroblasts containing excess MT was also normal. The data suggest that one function of the protein associated with the primary defect is to help determine how much copper is taken up and retained by fibroblasts and other cell types exhibiting the excess copper phenotype in Menkes disease. The capacity of this protein is apparently exceeded in normal fibroblasts if serum or albumin is not present extracellularly to limit total copper uptake. Consistent with a defect in an intracellular protein, the kinetics of copper transport by brindled mice fibroblasts were found to be normal.

Animals↗
PubMed1999

TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.

Transforming growth factor-beta1 (TGF-beta1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-beta1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-beta1] consisting of the cDNA coding for an activated form of TGF-beta1 under the control of the regulatory elements of the inducible human CRP gene promoter. Two transgenic lines were generated with liver-specific overexpression of mature TGF-beta1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 microgram ip), plasma TGF-beta1 levels reached >600 ng/ml in transgenic animals, which is >100 times above normal plasma levels. Basal plasma levels of uninduced transgenic animals were about two to five times above normal. As a consequence of hepatic TGF-beta1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-beta1 expression. Liver histology after repeated induction of transgene expression showed an activation of hepatic stellate cells in both transgenic lines. The fibrotic process was characterized by perisinusoidal deposition of collagen in a linear pattern. This transgenic mouse model gives in vivo evidence for the important role of TGF-beta1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-beta1 expression, this model allows the study of the regulation and kinetics of collagen synthesis and fibrolysis as well as the degree of reversibility of liver fibrosis. The CRP/TGF-beta1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.

Animals↗
PubMed1997

Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment.

The GM2 activator deficiency (also known as the AB variant), Tay-Sachs disease, and Sandhoff disease are the major forms of the GM2 gangliosidoses, disorders caused by defective degradation of GM2 ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. The GM2 activator deficiency is caused by mutations in the GM2A gene encoding the GM2 activator protein. For degradation of GM2 ganglioside by beta-hexosamindase A, the GM2 activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, GM2 ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the GM2 activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of GM2 with a low amount of GA2. The results demonstrate that the activator protein is required for GM2 degradation and also may indicate a role for the GM2 activator in GA2 degradation.

Animals↗
PubMed1989

Radioimmunoscintigraphy and radioimmunotherapy in nude mouse models. Studies with site-specifically modified monoclonal antibodies.

Site-specific covalent modification of monoclonal antibodies at the oligosaccharide offers advantages over more conventional modification processes that involve direct attachment at tyrosine, lysine or glutamic/aspartic acid side chains. Using the site-specific modification process, attachment sites on the antibody are distal to the antigen-binding region. Thus, homogeneity of antigen-binding properties and affinity for the unmodified protein are preserved. Furthermore, higher derivatization ratios with no resultant loss of immunoreactivity can be achieved for monoclonal antibodies modified at the oligosaccharide. In vivo biodistribution and tumor localization studies in nude mouse models suggest that antibodies radiolabeled at their oligosaccharide might represent improved immunoscintigraphic reagents. In a variety of tumor xenograft models, site-specific modified 111In-labeled antibody conjugates localized to the tumor site with little non-specific localization in other tissues or organs. The degree of localization at the target site was substantially greater than that of 111In-labeled antibodies directly modified at the tyrosine side chain. Preliminary studies with 212Bi- and 90Y-labeled antibodies modified at the oligosaccharide indicate that both of these radioisotopes have immunotherapeutic potential. Because of its preferential uptake by the kidney, the use of 212Bi may be best suited for tumors localized within the peritoneal cavity, such as ovarian and colorectal carcinomas. The toxicity of 90Y at high specific activities suggests that a regimen of repeated smaller doses of this radioisotope is best suited for therapeutic use. Studies in tumor-bearing mouse models are currently underway to better define the optimal dosage and administration regimens for both of these radioisotopes when attached to site-specific modified antibodies.

Animals↗