Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates.

ABSTRACT: Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (?-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human ?-Gal A in wild-type (WT) mice, ?-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-?-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of ?-Gal A in tissues and plasma. Single intravenous administration of h-?-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-?-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.

SUBMITTER: Zhu X

PROVIDER: S-EPMC6451694 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.

Project description:Preclinical studies of enzyme-replacement therapy for Fabry disease (deficient alpha-galactosidase A [alpha-Gal A] activity) were performed in alpha-Gal A-deficient mice. The pharmacokinetics and biodistributions were determined for four recombinant human alpha-Gal A glycoforms, which differed in sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were approximately 2-5 min, with the more sialylated glycoforms circulating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with detectable activity in other tissues but not in the brain. Normal or greater activity levels were reconstituted in various tissues after repeated doses (10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 glycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinjection. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repeated doses (every 48 h for eight doses) of AGA-1 at 0.3-10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in other tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for > or =4 wk, whereas cardiac and splenic GL-3 reaccumulated at 3 wk to approximately 30% and approximately 10% of pretreatment levels, respectively. Ultrastructural studies demonstrated reduced GL-3 storage posttreatment. These preclinical animal studies demonstrate the dose-dependent clearance of tissue and plasma GL-3 by administered alpha-Gal A, thereby providing the in vivo rationale-and the critical pharmacokinetic and pharmacodynamic data-for the design of enzyme-replacement trials in patients with Fabry disease.

| S-EPMC1234907 | biostudies-literature

Systemic administration of heparin ameliorates radiation-induced oral mucositis-preclinical studies in mice.

Project description:PurposeThe present study investigates the impact of systemic application of heparins on the manifestation of radiation-induced oral mucositis in a well-established mouse model.Materials and methodsMale C3H/Neu mice were irradiated with either single-dose or fractionated irradiation protocols with 5 × 3 Gy/week, given over one (days 0-4) or two (days 0-4, 7-11) weeks. All fractionation protocols were concluded by a local test irradiation (day 7/14) using graded doses to generate complete dose-effect curves. Daily doses of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively) were applied subcutaneously over varying time intervals. The incidence and the time course of mucosal ulceration, corresponding to confluent mucositis in patients (RTOG/EORTC grade 3), were analysed as clinically relevant endpoints.ResultsSystemic application of heparins significantly increased the iso-effective doses for the induction of mucosal ulceration, particularly in combination with fractionated irradiation protocols. Moreover, a tentative prolongation of the latent time and a pronounced reduction of the ulcer duration were observed.ConclusionThese data provide the first evidence for a protective and/or mitigative effect of heparins for radiation-induced oral mucositis. Further studies are ongoing investigating the underlying mechanism.

| S-EPMC6008356 | biostudies-literature

Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries.

Project description:IntroductionFreeze-dried black raspberries (BRBs) elicit chemopreventive effects against colorectal cancer in humans and in rodents. The objective of this study was to investigate potential BRB-caused metabolite changes using wild-type (WT) C57BL/6 mice.Methods and resultsWT mice were fed either control diet or control diet supplemented with 5% BRBs for 8 wk. A nontargeted metabolomic analysis was conducted on colonic mucosa, liver, and fecal specimens collected from both diet groups. BRBs significantly changed the levels of 41 colonic mucosa metabolites, 40 liver metabolites, and 34 fecal metabolites compared to control diet-fed mice. BRBs reduced 34 lipid metabolites in colonic mucosa and increased levels of amino acids in liver. One metabolite, 3-[3-(sulfooxy) phenyl] propanoic acid, might be a useful biomarker of BRB consumption. In addition, BRB powder was found to contain 30-fold higher levels of linolenate compared to control diets. Consistently, multiple omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including stearidonate, docosapentaenoate (ω-3 DPA), eicosapentaenoate (EPA), and docosahexaenoate (DHA), were significantly elevated in livers of BRB-fed mice.ConclusionThe data from the current study suggest that BRBs produce systemic metabolite changes in multiple tissue matrices, supporting our hypothesis that BRBs may serve as both a chemopreventive agent and a beneficial dietary supplement.

| S-EPMC5644389 | biostudies-literature

Human parainfluenza virus type 3 in wild nonhuman primates, Zambia.

Project description:Human parainfluenza virus type 3 (HPIV3) genome was detected in 4 baboons in Zambia. Antibody for HPIV3 was detected in 13 baboons and 6 vervet monkeys in 2 distinct areas in Zambia. Our findings suggest that wild nonhuman primates are susceptible to HPIV3 infection.

| S-EPMC3810902 | biostudies-literature

Immune competency of a hairless mouse strain for improved preclinical studies in genetically engineered mice.

Project description:Genetically engineered mouse models (GEMM) of cancer are of increasing value to preclinical therapeutics. Optical imaging is a cost-effective method of assessing deep-seated tumor growth in GEMMs whose tumors can be encoded to express luminescent or fluorescent reporters, although reporter signal attenuation would be improved if animals were fur-free. In this study, we sought to determine whether hereditable furlessness resulting from a hypomorphic mutation in the Hairless gene would or would not also affect immune competence. By assessing humoral and cellular immunity of the SKH1 mouse line bearing the hypomorphic Hairless mutation, we determined that blood counts, immunoglobulin levels, and CD4+ and CD8+ T cells were comparable between SKH1 and the C57Bl/6 strain. On examination of T-cell subsets, statistically significant differences in naïve T cells (1.7 versus 3.4 x 10(5) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) and memory T cells (1.4 versus 0.13 x 10(6) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) were detected. However, the numerical differences did not result in altered T-cell functional response to antigen rechallenge (keyhole limpet hemocyanin) in a lymph node cell in vitro proliferative assay. Furthermore, interbreeding the SKH1 mouse line to a rhabdomyosarcoma GEMM showed preserved antitumor responses of CD56+ natural killer cells and CD163+ macrophages, without any differences in tumor pathology. The fur-free GEMM was also especially amenable to multiplex optical imaging. Thus, SKH1 represents an immune competent, fur-free mouse strain that may be of use for interbreeding to other genetically engineered mouse models of cancer for improved preclinical studies.

| S-EPMC2921575 | biostudies-literature

Microarray profiling of miRNA and mRNA expression in Rag2 knockout and wild-type mouse spleens.

Project description:The Rag2 knockout (KO) mouse is one of the most popular immune compromised animal models used in biomedical research. The immune compromised state concurrently alters many signalling pathways and molecules, including miRNAs and mRNA transcripts that are involved in important biological processes. In addition, miRNAs and transcripts are interdependent, often forming a feedback loop; dysregulation in one might alter the expression of the other, and both participate in many physiological processes including immune regulation. Here, we describe a comprehensive dataset containing alterations in the expression of both miRNAs and mRNAs in Rag2 KO mice compared to their wild type counterparts. The miRNA and mRNA expression profiles were generated from total RNA using a miRNA expression microarray or a BeadChip microarray, respectively. Hence, this dataset will provide the groundwork for a comparative study of the miRNAs and mRNAs that are dysregulated in Rag2 KO mice. It is hoped that the data will illuminate how miRNAs mediate immune regulation, as well as the interaction between miRNAs and mRNAs in Rag2 KO mice.

| S-EPMC5759371 | biostudies-literature

Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies.

Project description:Most patients (70-90%) with the multiple endocrine neoplasia type 1 (MEN1) syndrome possess germline heterozygous mutations in MEN1 that predisposes to tumors of multiple endocrine and nonendocrine tissues. Some endocrine tumors of the kinds seen in MEN1 that occur sporadically in the general population also possess somatic mutations in MEN1. Interestingly, the endocrine tumors of MEN1 are recapitulated in mouse models of Men1 loss that serve as a valuable resource to understand the pathophysiology and molecular basis of tumorigenesis. Exploring these endocrine tumors in mouse models using in vivo, ex vivo and in vitro methods can help to follow the process of tumorigenesis, and can be useful for preclinical testing of therapeutics and understanding their mechanisms of action.

| S-EPMC4327775 | biostudies-literature

Methylation studies in strepsirrhini primates

Project description:DNA methylation data from several primate species profiled on the mammalian methylation array (HorvathMammalMethylChip40) which focuses on highly conserved CpGs across mammalian species. We selected a total of 91 samples from animals representing 26 strepsirrhine species, in most cases, the entire lifespan, from immature (infant or juvenile) to senile stages: 68 samples from peripheral blood, 23 samples from skin Blood and skin samples from many different primates. We profiled the following species: Cheirogaleus medius (Fat-tailed dwarf lemur), Daubentonia madagascariensis (Aye-aye), Eulemur albifrons (White-headed lemur), Eulemur collaris (Collared brown lemur), Eulemur coronatus (Crowned lemur), Eulemur flavifrons (Blue-eyed black lemur), Eulemur fulvus (Brown lemur), Eulemur macaco (Black lemur), Eulemur mongoz (Mongoose lemur), Eulemur rubriventer (Red-bellied lemur), Eulemur rufus (Red-fronted lemur), Eulemur sanfordi (Sanford's brown lemur), Galago moholi (South African galago), Hapalemur griseus (Bamboo lemur), Lemur catta (Ring-tailed lemur), Loris tardigradus (Slender loris), Microcebus murinus (Gray mouse lemur), Mirza zaza (Northern giant mouse lemur), Nycticebus coucang (Slow loris), Otolemur crassicaudatus (Greater galago), Perodicticus potto (Potto), Propithecus diadema (Diademed sifaka), Propithecus tattersalli (Golden-crowned sifaka), Varecia rubra (Red ruffed lemur). Peripheral blood was collected through venipuncture with standard procedures, either during a routine veterinary procedure or at time of necropsy. Skin tissues were collected during necropsies.

2023-08-05 | GSE190662 | GEO

Transcriptome and proteome analysis of Salmonella enterica serovar Typhimurium systemic infection of wild type and immune-deficient mice.

Project description:Salmonella enterica are a threat to public health. Current vaccines are not fully effective. The ability to grow in infected tissues within phagocytes is required for S. enterica virulence in systemic disease. As the infection progresses the bacteria are exposed to a complex host immune response. Consequently, in order to continue growing in the tissues, S. enterica requires the coordinated regulation of fitness genes. Bacterial gene regulation has so far been investigated largely using exposure to artificial environmental conditions or to in vitro cultured cells, and little information is available on how S. enterica adapts in vivo to sustain cell division and survival. We have studied the transcriptome, proteome and metabolic flux of Salmonella, and the transcriptome of the host during infection of wild type C57BL/6 and immune-deficient gp91-/-phox mice. Our analyses advance the understanding of how S. enterica and the host behaves during infection to a more sophisticated level than has previously been reported.

| S-EPMC5552096 | biostudies-literature

Microbiome Composition in Both Wild-Type and Disease Model Mice Is Heavily Influenced by Mouse Facility.

Project description:Murine models have become essential tools for understanding the complex interactions between gut microbes, their hosts, and disease. While many intra-facility factors are known to influence the structure of mouse microbiomes, the contribution of inter-facility variation to mouse microbiome composition, especially in the context of disease, remains under-investigated. We replicated microbiome experiments using identical mouse lines housed in two separate animal facilities and report drastic differences in composition of microbiomes based upon animal facility of origin. We observed facility-specific microbiome signatures in the context of a disease model [the Ednrb (endothelin receptor type B) Hirschsprung disease mouse] and in normal C57BL/6J mice. Importantly, these facility differences were independent of cage, sex, or sequencing-related influence. In addition, we investigated the reproducibility of microbiome dysbiosis previously associated with Ednrb-/- (knock-out; KO) mice. While we observed genotype-based differences in composition between wild-type (WT) and KO mice, these differences were inconsistent with the previously reported conclusions. Furthermore, the genotype-based differences were not identical across animal facilities. Despite this, through differential abundance testing, we identified several conserved candidate taxa and candidate operational taxonomic units that may play a role in disease promotion or protection. Overall, our findings raise the possibility that previously reported microbiome-disease associations from murine studies conducted in a single facility may be heavily influenced by facility-specific effects. More generally, these results provide a strong rationale for replication of mouse microbiome studies at multiple facilities, and for the meticulous collection of metadata that will allow the confounding effects of facility to be more specifically identified.

| S-EPMC6062620 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data