WAUWATOSA, WI, United States
WAUWATOSA, WI, United States
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Maciejewski B.S.,Pfizer | LaPerle J.L.,Pfizer | Chen D.,Pfizer | Ghosh A.,Pfizer | And 13 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2013

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption. © 2013 the American Physiological Society.

Maga J.A.,ZyStor Therapeutics | Zhou J.,ZyStor Therapeutics | Zhou J.,Oncode Med Inc. | Kambampati R.,ZyStor Therapeutics | And 11 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Acid-glucosidase, an enzyme replacement therapy for Pompe disease, is poorly targeted to lysosomes when relying on phosphomannose residues. Results: Fusing IGF-II to acid α-glucosidase resulted in more efficient uptake and glycogen clearance from muscle of Pompe mice. Conclusion: Enhanced binding to the cation-independent mannose 6-phosphate receptor (CI-MPR) enabled improved glycogen clearance in Pompe mice. Significance: BMN 701 is now being tested for Pompe disease in human clinical studies. We have used a peptide-based targeting system to improve lysosomal delivery of acid-glucosidase (GAA), the enzyme deficient in patients with Pompe disease. Human GAA was fused to the glycosylation-independent lysosomal targeting (GILT) tag, which contains a portion of insulin-like growth factor II, to create an active, chimeric enzyme with high affinity for the cation-independent mannose 6-phosphate receptor. GILTtagged GAA was taken up by L6 myoblasts about 25-fold more efficiently than was recombinant human GAA (rhGAA). Once delivered to the lysosome, the mature form of GILT-taggedGAA was indistinguishable from rhGAA and persisted with a half-life indistinguishable from rhGAA. GILT-tagged GAA was significantly more effective than rhGAA in clearing glycogen from numerous skeletal muscle tissues in the Pompe mouse model. The GILT-tagged GAA enzyme may provide an improved enzyme replacement therapy for Pompe disease patients. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Williams J.M.,University of Mississippi Medical Center | Zhang J.,University of Mississippi Medical Center | North P.,Medical College of Wisconsin | Lacy S.,Exelixis | And 3 more authors.
American Journal of Physiology - Renal Physiology | Year: 2011

This study examined the effects of two new selective metalloprotease (MMP) inhibitors, XL081 and XL784, on the development of renal injury in rat models of hypertension, Dahl salt-sensitive (Dahl S) and type 2 diabetic nephropathy (T2DN). Protein excretion rose from 20 to 120 mg/day in Dahl S rats fed a high-salt diet (8.0% NaCl) for 4 wk to induce hypertension. Chronic treatment with XL081 markedly reduced proteinuria and glomerulosclerosis, but it also attenuated the development of hypertension. To determine whether an MMP inhibitor could oppose the progression of renal damage in the absence of changes in blood pressure, Dahl S rats were fed a high-salt diet (4.0% NaCl) for 5 wks to induce renal injury and then were treated with the more potent and bioavailable MMP inhibitor XL784 either given alone or in combination with lisinopril and losartan. Treatment with XL784 or the ANG II blockers reduced proteinuria and glomerulosclerosis by ~30% and had no effect on blood pressure. Proteinuria fell from 150 to 30 mg/day in the rats receiving both XL784 and the ANG II blockers, and the degree of renal injury fell to levels seen in normotensive Dahl S rats maintained from birth on a low-salt diet. In other studies, albumin excretion rose from 125 to >200 mg/day over a 4-mo period in 12-mo-old uninephrectomized T2DN rats. In contrast, albumin excretion fell by >50% in T2DN rats treated with XL784, lisinopril, or combined therapy. XL784 reduced the degree of glomerulosclerosis in the T2DN rats to a greater extent than lisinopril, and combined therapy was more effective than either drug alone. These results indicate that chronic administration of a selective MMP inhibitor delays the progression, and may even reverse hypertension and diabetic nephropathy © 2011 the American Physiological Society.

Yang Y.,Abbott Laboratories | Dahly-Vernon A.J.,Physiogenix, Inc. | Blomme E.A.G.,Abbott Laboratories | Lai-Zhang J.,Abbott Laboratories | And 10 more authors.
Veterinary Journal | Year: 2010

Ritonavir (RTV) and other protease inhibitors (PIs) used for the treatment of human immunodeficiency virus (HIV) infection are associated with elevated serum triglycerides (TG) and cholesterol in some patients. A rat strain (Sprague-Dawley or SD) commonly used in toxicology studies is not sensitive to RTV-induced hyperlipidemia, making mechanistic studies and the identification of novel, lipid-neutral PIs challenging. The objective of this study was to identify a rat strain that mirrors human PI-associated hyperlipidemia. RTV was administered at 100. mg/kg/day for 5. days to a panel of 14 rat strains estimated to cover approximately 86% of the known genetic variance in rats. Increased serum TG and cholesterol levels occurred only in two rat strains, including LEW × BN rats. Livers from LEW × BN (sensitive) and SD (resistant) rats were then evaluated using microarrays to investigate differences in the transcriptomic response to RTV.Several genes, including some involved in bile acid biosynthesis, gluconeogenesis, and carbohydrate metabolism, were differentially regulated between the two strains. In particular, cytochrome P450 7A1 (CYP7A1), a key enzyme for cholesterol metabolism, was down-regulated in the sensitive and up-regulated in resistant rats. Collectively, these results demonstrate the utility of a genetically diverse rat panel to identify strains with clinical relevance for a particular adverse effect. Furthermore, the genome-wide transcriptomic analysis suggests that RTV-induced hyperlipidemia is at least in part due to changes in hepatic lipid biosynthesis and metabolism. These findings will facilitate the discovery of novel, lipid-neutral HIV PIs and the identification of relevant biomarkers for this adverse event. © 2010 Elsevier Ltd.

Kerr A.L.,Garland Power and Light | Kerr A.L.,University of Wisconsin - Milwaukee | Hensel M.L.,Garland Power and Light | Hensel M.L.,University of Wisconsin - Milwaukee | And 7 more authors.
Behavior Genetics | Year: 2010

The present study was conducted in an effort to evaluate whether chromosomal substitution can repair impaired exploration learning and memory. It has previously been observed that Dahl salt-sensitive (SS) rodents exhibit impaired cognitive function along with abnormal physiological responses to muscle stimulation. Introgression of Brown Norway chromosome (13BN) has been found to restore normal physiological processes in SS animals. However, the effect of chromosomal substitution on cognitive performance has not been explored. It was hypothesized that 13BN also rescues cognitive impairments in these animals. Visual spatial learning and cognitive flexibility were evaluated using the Morris water maze (MWM) and the T-maze. This manipulation is effective in rescuing impaired task acquisition, but not perseveration observed in the SS animal. These animals may represent a natural animal model in which to isolate genetic information responsible for learning and memory function. © 2009 Springer Science+Business Media, LLC.

Jarome T.J.,University of Wisconsin - Milwaukee | Kwapis J.L.,University of Wisconsin - Milwaukee | Nye S.H.,Physiogenix, Inc. | Helmstetter F.J.,University of Wisconsin - Milwaukee
Behavior Genetics | Year: 2010

The isolation of genes influencing long-term memory is critical for an understanding of learning at the molecular level. Recently, chromosomal substitution rat strains, known as consomics, have been developed. Here we report the results of the first study on aversive learning and memory with these consomic rats. We compared the Fawn Hooded Hypertensive (FHH) and Brown Norway (BN) parent strains with a Brown Norway chromosome 1 substitution on the FHH background (FHH-1BN). Results indicated that while all strains had normal short-term memory, the FHH animals were impaired relative to BN in tests of long-term memory for a discrete auditory cue. This deficit was rescued by the introgression of the BN1 chromosome onto the FHH background. Furthermore, the FHH-1BN consomic showed an enhancement in long-term contextual fear memory relative to the FHH strain. These changes were not due to differences in pain sensitivity as both strains performed equally on two different pain tests. These results provide preliminary support that consomic rat strains can be a useful tool in identifying genes related to long-term fear memory formation. © 2009 Springer Science+Business Media, LLC.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 343.80K | Year: 2010

DESCRIPTION (provided by applicant): The number of patients in the United States afflicted with learning and memory disorders is rapidly increasing. This necessitates the development of new, better acting and safer medications for enhancing cognition. In this SBIR Phase I project, PhysioGenix will determine the efficacy, pharmacokinetics (PK), maximum tolerated dose and potential side-effects of PWZ-029, a benzodiazepine (BZ) compound that may prove useful for treating patients with learning and memory disorders. BZs are listed as a Core Medicine in the WHO Essential Drug List and those on the market, such as Valium and Xanax, are widely used for the treatment of anxiety, panic attacks, insomnia, agitation and seizures. BZs can cause depressing (agonist) or stimulating (inverse agonist) effects on the central nervous system by modulating the GABAA receptor, the most prevalent inhibitory receptor within the brain. However, side-effects are common in patients treated with BZs and this can limit their use. For example, Valium is a full agonist of the GABAA receptor but has a side-effect profile in patients that includes sedation, amnesia and ataxia. Nonselective BZ inverse agonists, like DMCM, are often anxiogenic and can cause seizures in animals. Because these unwanted side-effects can be attributed to nonspecific interactions of the BZs for different subunits of the GABAA receptor complex, functionally specific BZs that retain only the desired pharmacological response are being developed. GABAA receptor complexes that contain 15 subunits are abundantly expressed in the hippocampus and therefore considered to be a therapeutic target for treating cognitive disorders, like Alzheimer's and ADHD. With this in mind, PWZ-029 was designed by Dr. James Cook of the University of Wisconsin-Milwaukee, to be an inverse agonist for the GABAA receptor having subtype and functional selectivity predominantly at the 15 subunit. Recent in vitro studies in oocytes have shown that PWZ-029 has up to 60-fold more functional selectivity for the 15 subunit compared to 11, 12 and 13. Behavior tests also suggest that PWZ-029 has cognition enhancing capabilities, thereby making it a feasible therapeutic candidate. Here, the ability of PWZ-029 to enhance cognition will be assessed in both rodents and rhesus monkeys. For rodent studies, the PK of PWZ-029 will be measured in blood and brain following oral administration to assess its bioavailability. Maximum tolerated dose studies will be carried out as part of lead optimization toxicology, which may also detect if PWZ-029 will cause seizures. The proconvulsant liability of PWZ-029 will be measured directly using the PTZ mouse model. The behavior tests will incorporate rat strains that have natural deficits in cognition along with a standard scopolamine amnesia model. Finally, rhesus monkey will be used to measure potential sedative side-effects along with confirming preliminary data for the ability of PWZ-02 to enhance cognition. Success will lead to Phase II studies that will aim to expand preclinical safety and efficacy testing ultimately leading to clinical trials. Commercialization opportunities will be realized via drug development efforts for treating mental health disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies that determine the bioavailability and safety of functionally selective benzodiazepine compounds, like PWZ-029, are required prior to further drug development. Screening of compounds with relevant disease models will help to assess their therapeutic potential. Patients with learning disorders and those suffering from complications due to neurodegenerative diseases will greatly benefit as PWZ-029 moves another step closer to the clinic.

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