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1. Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02)

Author

Byrne, Barry J., Schoser, Benedikt, Kishnani, Priya S., Bratkovic, Drago, Clemens, Paula R., Goker-Alpan, Ozlem, Ming, Xue, Roberts, Mark, Vorgerd, Matthias, Sivakumar, Kumaraswamy, van der Ploeg, Ans T., Goldman, Mitchell, Wright, Jacquelyn, Holdbrook, Fred, Jain, Vipul, Benjamin, Elfrida R., Johnson, Franklin, Das, Sheela Sitaraman, Wasfi, Yasmine, and Mozaffar, Tahseen

Published
2024
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2. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study

Author

Hughes, Derralynn A, Nicholls, Kathleen, Shankar, Suma P, Sunder-Plassmann, Gere, Koeller, David, Nedd, Khan, Vockley, Gerard, Hamazaki, Takashi, Lachmann, Robin, Ohashi, Toya, Olivotto, Iacopo, Sakai, Norio, Deegan, Patrick, Dimmock, David, Eyskens, François, Germain, Dominique P, Goker-Alpan, Ozlem, Hachulla, Eric, Jovanovic, Ana, Lourenco, Charles M, Narita, Ichiei, Thomas, Mark, Wilcox, William R, Bichet, Daniel G, Schiffmann, Raphael, Ludington, Elizabeth, Viereck, Christopher, Kirk, John, Yu, Julie, Johnson, Franklin, Boudes, Pol, Benjamin, Elfrida R, Lockhart, David J, Barlow, Carrolee, Skuban, Nina, Castelli, Jeffrey P, Barth, Jay, and Feldt-Rasmussen, Ulla

Subjects
Pediatric, Neurodegenerative, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Orphan Drug, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 1-Deoxynojirimycin, Administration, Oral, Adolescent, Adult, Aged, Enzyme Replacement Therapy, Fabry Disease, Female, Humans, Lysosomes, Male, Middle Aged, Molecular Chaperones, Treatment Outcome, alpha-Galactosidase, Fabry disease, Pharmacological chaperone, enzyme replacement therapy, lyso-Gb3, lysosomal storage disorder, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration numberNCT00925301; Pre-results.

Published
2017

3. Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease:an open-label phase I/II study (ATB200-02)

Author

Byrne, Barry J., Schoser, Benedikt, Kishnani, Priya S., Bratkovic, Drago, Clemens, Paula R., Goker-Alpan, Ozlem, Ming, Xue, Roberts, Mark, Vorgerd, Matthias, Sivakumar, Kumaraswamy, van der Ploeg, Ans T., Goldman, Mitchell, Wright, Jacquelyn, Holdbrook, Fred, Jain, Vipul, Benjamin, Elfrida R., Johnson, Franklin, Das, Sheela Sitaraman, Wasfi, Yasmine, Mozaffar, Tahseen, Byrne, Barry J., Schoser, Benedikt, Kishnani, Priya S., Bratkovic, Drago, Clemens, Paula R., Goker-Alpan, Ozlem, Ming, Xue, Roberts, Mark, Vorgerd, Matthias, Sivakumar, Kumaraswamy, van der Ploeg, Ans T., Goldman, Mitchell, Wright, Jacquelyn, Holdbrook, Fred, Jain, Vipul, Benjamin, Elfrida R., Johnson, Franklin, Das, Sheela Sitaraman, Wasfi, Yasmine, and Mozaffar, Tahseen

Abstract

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2–6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL − 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; − 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Published
2024

4. Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02)

Author

Byrne, Barry J., primary, Schoser, Benedikt, additional, Kishnani, Priya S., additional, Bratkovic, Drago, additional, Clemens, Paula R., additional, Goker-Alpan, Ozlem, additional, Ming, Xue, additional, Roberts, Mark, additional, Vorgerd, Matthias, additional, Sivakumar, Kumaraswamy, additional, van der Ploeg, Ans T., additional, Goldman, Mitchell, additional, Wright, Jacquelyn, additional, Holdbrook, Fred, additional, Jain, Vipul, additional, Benjamin, Elfrida R., additional, Johnson, Franklin, additional, Das, Sheela Sitaraman, additional, Wasfi, Yasmine, additional, and Mozaffar, Tahseen, additional

Published
2023
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6. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Author

Benjamin, Elfrida R., Della Valle, Maria Cecilia, Wu, Xiaoyang, Katz, Evan, Pruthi, Farhana, Bond, Sarah, Bronfin, Benjamin, Williams, Hadis, Yu, Julie, Bichet, Daniel G., Germain, Dominique P., Giugliani, Roberto, Hughes, Derralynn, Schiffmann, Raphael, Wilcox, William R., Desnick, Robert J., Kirk, John, Barth, Jay, Barlow, Carrolee, Valenzano, Kenneth J., Castelli, Jeff, and Lockhart, David J.

Published
2017
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7. Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice

Author

Xu, Su, Lun, Yi, Brignol, Nastry, Hamler, Rick, Schilling, Adriane, Frascella, Michelle, Sullivan, Sean, Boyd, Robert E, Chang, Kate, Soska, Rebecca, Garcia, Anadina, Feng, Jessie, Yasukawa, Hidehito, Shardlow, Carole, Churchill, Alison, Ketkar, Amol, Robertson, Nicola, Miyamoto, Masahito, Mihara, Kazutoshi, Benjamin, Elfrida R, Lockhart, David J, Hirato, Tohru, Fowles, Susie, Valenzano, Kenneth J, and Khanna, Richie

Published
2015
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13. State-dependent compound inhibition of [Na.sub.v]1.2 sodium channels using the FLIPR [V.sub.m] Dye: on-target and off-target effects of diverse pharmacological agents

Author

Benjamin, Elfrida R., Pruthi, Farhana, Olanrewaju, Shakira, Ilyin, Victor I., Crumley, Gregg, Kutlina, Elena, Valenzano, Kenneth J., and Woodward, Richard M.

Subjects
Membrane potentials -- Research -- Analysis, Sodium channels -- Research -- Analysis, Fluorescence -- Analysis -- Research, Biological sciences, Analysis, Research
Abstract

Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors [...]

Published
2006

14. Validation of a fluorescent imaging plate reader membrane potential assay for high-throughput screening of glycine transporter modulators

Author

Benjamin, Elfrida R., Skelton, Joanne, Hanway, Denise, Olanrewaju, Shakira, Pruthi, Farhana, Ilyin, Victor I., Lavery, Daniel, Victory, Sam F., and Valenzano, Kenneth J.

Subjects
Electrophysiology -- Research, Pharmacology, Experimental -- Research, Glycine -- Research, Biological sciences, Research
Abstract

A fluorescent imaging plate reader (FLIPR) membrane potential ([V.sub.m]) assay was evaluated for pharmacological characterization and high-throughput screening (HTS) of rat glycine transporter type 2 (rGly[T.sub.2]) in a stable rGly[T.sub.2]-HEK [...]

Published
2005

22. Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease

Author

Hamler, Rick, primary, Brignol, Nastry, additional, Clark, Sean W., additional, Morrison, Sean, additional, Dungan, Leo B., additional, Chang, Hui H., additional, Khanna, Richie, additional, Frascella, Michelle, additional, Valenzano, Kenneth J., additional, Benjamin, Elfrida R., additional, and Boyd, Robert E., additional

Published
2017
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23. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease:18-month results from the randomised phase III ATTRACT study

Author

Hughes, Derralynn A., Nicholls, Kathleen, Shankar, Suma P., Sunder-Plassmann, Gere, Koeller, David, Nedd, Khan, Vockley, Gerard, Hamazaki, Takashi, Lachmann, Robin, Ohashi, Toya, Olivotto, Iacopo, Sakai, Norio, Deegan, Patrick, Dimmock, David, Eyskens, François, Germain, Dominique P., Goker-Alpan, Ozlem, Hachulla, Eric, Jovanovic, Ana, Lourenco, Charles M., Narita, Ichiei, Thomas, Mark, Wilcox, William R., Bichet, Daniel G., Schiffmann, Raphael, Ludington, Elizabeth, Viereck, Christopher, Kirk, John, Yu, Julie, Johnson, Franklin, Boudes, Pol, Benjamin, Elfrida R., Lockhart, David J., Barlow, Carrolee, Skuban, Nina, Castelli, Jeffrey P., Barth, Jay, Feldt-Rasmussen, Ulla, Hughes, Derralynn A., Nicholls, Kathleen, Shankar, Suma P., Sunder-Plassmann, Gere, Koeller, David, Nedd, Khan, Vockley, Gerard, Hamazaki, Takashi, Lachmann, Robin, Ohashi, Toya, Olivotto, Iacopo, Sakai, Norio, Deegan, Patrick, Dimmock, David, Eyskens, François, Germain, Dominique P., Goker-Alpan, Ozlem, Hachulla, Eric, Jovanovic, Ana, Lourenco, Charles M., Narita, Ichiei, Thomas, Mark, Wilcox, William R., Bichet, Daniel G., Schiffmann, Raphael, Ludington, Elizabeth, Viereck, Christopher, Kirk, John, Yu, Julie, Johnson, Franklin, Boudes, Pol, Benjamin, Elfrida R., Lockhart, David J., Barlow, Carrolee, Skuban, Nina, Castelli, Jeffrey P., Barth, Jay, and Feldt-Rasmussen, Ulla

Abstract

Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α- Gal to facilitate normal lysosomal trafficking. Methods The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. Results Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had nonamenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. Conclusions Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.

Published
2017

25. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study

Author

Hughes, Derralynn A, primary, Nicholls, Kathleen, additional, Shankar, Suma P, additional, Sunder-Plassmann, Gere, additional, Koeller, David, additional, Nedd, Khan, additional, Vockley, Gerard, additional, Hamazaki, Takashi, additional, Lachmann, Robin, additional, Ohashi, Toya, additional, Olivotto, Iacopo, additional, Sakai, Norio, additional, Deegan, Patrick, additional, Dimmock, David, additional, Eyskens, François, additional, Germain, Dominique P, additional, Goker-Alpan, Ozlem, additional, Hachulla, Eric, additional, Jovanovic, Ana, additional, Lourenco, Charles M, additional, Narita, Ichiei, additional, Thomas, Mark, additional, Wilcox, William R, additional, Bichet, Daniel G, additional, Schiffmann, Raphael, additional, Ludington, Elizabeth, additional, Viereck, Christopher, additional, Kirk, John, additional, Yu, Julie, additional, Johnson, Franklin, additional, Boudes, Pol, additional, Benjamin, Elfrida R, additional, Lockhart, David J, additional, Barlow, Carrolee, additional, Skuban, Nina, additional, Castelli, Jeffrey P, additional, Barth, Jay, additional, and Feldt-Rasmussen, Ulla, additional

Published
2016
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26. Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat

Author

Germain, Dominique P., primary, Hughes, Derralynn A., additional, Nicholls, Kathleen, additional, Bichet, Daniel G., additional, Giugliani, Roberto, additional, Wilcox, William R., additional, Feliciani, Claudio, additional, Shankar, Suma P., additional, Ezgu, Fatih, additional, Amartino, Hernan, additional, Bratkovic, Drago, additional, Feldt-Rasmussen, Ulla, additional, Nedd, Khan, additional, Sharaf El Din, Usama, additional, Lourenco, Charles M., additional, Banikazemi, Maryam, additional, Charrow, Joel, additional, Dasouki, Majed, additional, Finegold, David, additional, Giraldo, Pilar, additional, Goker-Alpan, Ozlem, additional, Longo, Nicola, additional, Scott, C. Ronald, additional, Torra, Roser, additional, Tuffaha, Ahmad, additional, Jovanovic, Ana, additional, Waldek, Stephen, additional, Packman, Seymour, additional, Ludington, Elizabeth, additional, Viereck, Christopher, additional, Kirk, John, additional, Yu, Julie, additional, Benjamin, Elfrida R., additional, Johnson, Franklin, additional, Lockhart, David J., additional, Skuban, Nina, additional, Castelli, Jeff, additional, Barth, Jay, additional, Barlow, Carrolee, additional, and Schiffmann, Raphael, additional

Published
2016
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27. The validation of pharmacogenetics in the identification of patients with Fabry disease for treatment with migalastat

Author

Benjamin, Elfrida R., primary, Valle, Cecilia Della, additional, Wu, Xiaoyang, additional, Katz, Evan, additional, Valenzano, Kenneth J., additional, Bichet, Daniel G., additional, Germain, Dominique, additional, Giugliani, Roberto, additional, Hughes, Derralynn, additional, Schiffmann, Raphael, additional, Wilcox, William R., additional, Yu, Julie, additional, Kirk, John, additional, Barth, Jay, additional, and Castelli, Jeff, additional

Published
2016
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28. Co-administration of the pharmacological chaperone AT2221 with a proprietary recombinant human acid alfa-glucosidase leads to greater plasma exposure and substrate reduction compared to alglucosidase alfa

Author

Khanna, Richie, primary, Xu, Su, additional, Hilliard, Deborah, additional, Lun, Yi, additional, Schilling, Adriane, additional, Soska, Rebecca, additional, Nair, Anju, additional, Chang, Kate, additional, Feng, Jessie, additional, Frascella, Michelle, additional, Garcia, Anadina, additional, Pendino, Kimberly, additional, Johnson, Franklin, additional, Benjamin, Elfrida R., additional, Gotschall, Russell, additional, Do, Hung, additional, and Valenzano, Kenneth J., additional

Published
2016
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29. Accurate quantitation of plasma globotriaosylsphingosine (lyso-Gb3) in normal individuals and Fabry disease patients by liquid chromatography–tandem mass spectrometry (LC–MS/MS)

Author

Hamler, Rick, primary, Brignol, Nastry, additional, Boyd, Robert E., additional, Bichet, Daniel G., additional, Germain, Dominique P., additional, Giugliani, Roberto, additional, Hughes, Derralyn A., additional, Schiffmann, Raphael, additional, Wilcox, William R., additional, Williams, Hadis N., additional, Yu, Julie, additional, Barth, Jay, additional, Castelli, Jeff, additional, Valenzano, Kenneth J., additional, and Benjamin, Elfrida R., additional

Published
2015
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30. The Pharmacological Chaperone Isofagomine Increases Activity of the Gaucher Disease L444P Mutant Form of β-Glucosidase

Author

Khanna, Richie, Benjamin, Elfrida R., Pellegrino, Lee, Schilling, Adriane, Rigat, Brigitte A., Soska, Rebecca, Nafar, Hadis, Ranes, Brian E., Feng, Jessie, Lun, Yi, Powe, Allan C., Palling, David J., Wustman, Brandon A., Schiffmann, Raphael, Mahuran, Don J., Lockhart, David J., and Valenzano, Kenneth J.

Subjects
Male, Gaucher Disease, Microscopy, Confocal, endocrine system diseases, Dose-Response Relationship, Drug, beta-Glucosidase, nutritional and metabolic diseases, Fibroblasts, Article, Rats, Lysosomal Storage Diseases, Rats, Sprague-Dawley, Mice, Mutation, Animals, Glucosylceramidase, Humans, Imino Pyranoses, Molecular Chaperones
Abstract

Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid beta-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5- and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2- to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease.

Published
2010

32. Glucosylceramide and glucosylsphingosine quantitation by liquid chromotography-tandem mass spectrometry to enable studies of neuronopathic Gaucher disease

Author

Hamler, Rick, primary, Brignol, Nastry, additional, Morrison, Sean, additional, Hui, Chang H., additional, Dungan, Leo, additional, Boyd, Robert E., additional, Clark, Sean W., additional, Khanna, Richie, additional, Wustman, Brandon W., additional, Flanagan, John F., additional, Valenzano, Kenneth J., additional, Lockhart, David L., additional, and Benjamin, Elfrida R., additional

Published
2014
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33. Strategy to assess the effect of duvoglustat co-administered with alglucosidase alfa infusion on the immune response to enzyme replacement therapy for Pompe disease

Author

Benjamin, Elfrida R., primary, Wu, Xiaoyang, additional, Valle, M. Cecilia Della, additional, Sjoberg, Eric, additional, Sitaraman, Sheela, additional, Stevens, Anthony, additional, Gomez, Nestor, additional, Katz, Evan, additional, Pruthi, Farhana, additional, Kelley, Jeffry S., additional, Wustman, Brandon, additional, Valenzano, Kenneth J., additional, Byrne, Barry J., additional, Barlow, Carrolee, additional, and Lockhart, David J., additional

Published
2014
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34. Risk of Death in Heart Disease is Associated With Elevated Urinary Globotriaosylceramide

Author

Schiffmann, Raphael, primary, Forni, Sabrina, additional, Swift, Caren, additional, Brignol, Nastry, additional, Wu, Xiaoyang, additional, Lockhart, David J., additional, Blankenship, Derek, additional, Wang, Xuan, additional, Grayburn, Paul A., additional, Taylor, Matthew R. G., additional, Lowes, Brian D., additional, Fuller, Maria, additional, Benjamin, Elfrida R., additional, and Sweetman, Lawrence, additional

Published
2014
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36. Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb3) in Fabry Transgenic Mice and in the Plasma of Fabry Patients

Author

Young-Gqamana, Brandy, primary, Brignol, Nastry, additional, Chang, Hui-Hwa, additional, Khanna, Richie, additional, Soska, Rebecca, additional, Fuller, Maria, additional, Sitaraman, Sheela A., additional, Germain, Dominique P., additional, Giugliani, Roberto, additional, Hughes, Derralynn A., additional, Mehta, Atul, additional, Nicholls, Kathy, additional, Boudes, Pol, additional, Lockhart, David J., additional, Valenzano, Kenneth J., additional, and Benjamin, Elfrida R., additional

Published
2013
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38. A pharmacogenetic approach to identify mutant forms of α‐galactosidase a that respond to a pharmacological chaperone for Fabry disease

Author

Wu, Xiaoyang, primary, Katz, Evan, additional, Valle, Maria Cecilia Della, additional, Mascioli, Kirsten, additional, Flanagan, John J., additional, Castelli, Jeffrey P., additional, Schiffmann, Raphael, additional, Boudes, Pol, additional, Lockhart, David J., additional, Valenzano, Kenneth J., additional, and Benjamin, Elfrida R., additional

Published
2011
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40. Pharmacological chaperones aren't just for mutant enzymes anymore: Co-administration of AT1001 Stabilizes rh∂-Gal A, leading to greater uptake and substrate reduction in fabry patient-derived cells and GLA knockout mice

Author

Khanna, Richie, primary, Benjamin, Elfrida R., additional, Flanagan, John J., additional, Pellegrino, Lee, additional, Schilling, Adriane, additional, Chang, Kate, additional, Frascella, Michelle, additional, Lun, Yi, additional, Adera, Mathews, additional, Greene, Douglas, additional, Lockhart, David J., additional, and Valenzano, Kenneth J., additional

Published
2011
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44. Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLAmutations following 6 months of migalastat treatment

Author

Mauer, Michael, Sokolovskiy, Alexey, Barth, Jay A, Castelli, Jeffrey P, Williams, Hadis N, Benjamin, Elfrida R, and Najafian, Behzad

Abstract

ObjectiveDeficiency of α-galactosidase A (αGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA(α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease.Methods and analysisWe compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods.ResultsMigalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury.ConclusionMigalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

Published
2017
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45. Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb3) in Fabry Transgenic Mice and in the Plasma of Fabry Patients.

Author

Young-Gqamana, Brandy, Brignol, Nastry, Chang, Hui-Hwa, Khanna, Richie, Soska, Rebecca, Fuller, Maria, Sitaraman, Sheela A., Germain, Dominique P., Giugliani, Roberto, Hughes, Derralynn A., Mehta, Atul, Nicholls, Kathy, Boudes, Pol, Lockhart, David J., Valenzano, Kenneth J., and Benjamin, Elfrida R.

Subjects
ANGIOKERATOMA corporis diffusum, TRANSGENIC mice, GENETIC mutation, LIQUID chromatography-mass spectrometry, CLINICAL trials, PROTEOMICS
Abstract

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD. [ABSTRACT FROM AUTHOR]

Published
2013
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46. Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPR

Author

Benjamin, Elfrida R., Pruthi, Farhana, Olanrewaju, Shakira, Shan, Shen, Hanway, Denise, Liu, Xuesong, Cerne, Rok, Lavery, Daniel, Valenzano, Kenneth J., Woodward, Richard M., and Ilyin, Victor I.

Subjects
*PHARMACOLOGY, *ION channels, *FLUORESCENCE, *RADIOACTIVITY
Abstract

Abstract: The N-type voltage-gated calcium channel (Cav2.2) functions in neurons to regulate neurotransmitter release. It comprises a clinically relevant target for chronic pain. We have validated a calcium mobilization approach to assessing Cav2.2 pharmacology in two stable Cav2.2 cell lines: α1B, α2δ, β3-HEK-293 and α1B, β3-HEK-293. Cav2.2 channels were opened by addition of KCl and Ca2+ mobilization was measured by Fluo-4 fluorescence on a fluorescence imaging plate reader (FLIPR96). Cav2.2 expression and biophysics were confirmed by patch-clamp electrophysiology (EP). Both cell lines responded to KCl with adequate signal-to-background. Signals from both cell lines were inhibited by ω-conotoxin (ctx)-MVIIa and ω-conotoxin (ctx)-GVIa with IC50 values of 1.8 and 1nM, respectively, for the three-subunit stable, and 0.9 and 0.6nM, respectively, for the two-subunit stable. Other known Cav2.2 blockers were characterized including cadmium, flunarizine, fluspirilene, and mibefradil. IC50 values correlated with literature EP-derived values. Novel Cav2.2 pharmacology was identified in classes of compounds with other primary pharmacological activities, including Na+ channel inhibitors and antidepressants. Novel Na+ channel compounds with high potency at Cav2.2 were identified in the phenoxyphenyl pyridine, phenoxyphenyl pyrazole, and other classes. The highest potency at Cav2.2 tricyclic antidepressant identified was desipramine. [Copyright &y& Elsevier]

Published
2006
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47. State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR VmDye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

Author

Benjamin, Elfrida R., Pruthi, Farhana, Olanrewaju, Shakira, Ilyin, Victor I., Crumley, Gregg, Kutlina, Elena, Valenzano, Kenneth J., and Woodward, Richard M.

Abstract

Voltage-gated sodiumchannels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (V m)dyes in conjunctionwith a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR V massay of rat Na v1.2NaCh. Channels were opened by addition of veratridine, and Vm dye responses were measured. The IC50 values from various structural classes of compounds were compared to the resting state binding constant (K r)and inactivated state binding constant (K i)obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with Ki but not K r.FLIPRIC50 values fellwithin 0.1-to 1.5-fold of EPKi values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology.

Published
2006
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48. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase.

Author

Khanna R, Benjamin ER, Pellegrino L, Schilling A, Rigat BA, Soska R, Nafar H, Ranes BE, Feng J, Lun Y, Powe AC, Palling DJ, Wustman BA, Schiffmann R, Mahuran DJ, Lockhart DJ, and Valenzano KJ

Subjects
Animals, Dose-Response Relationship, Drug, Fibroblasts metabolism, Glucosylceramidase metabolism, Humans, Male, Mice, Microscopy, Confocal methods, Molecular Chaperones metabolism, Rats, Rats, Sprague-Dawley, Gaucher Disease genetics, Imino Pyranoses chemistry, Lysosomal Storage Diseases genetics, Mutation, beta-Glucosidase genetics
Abstract

Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid beta-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5- and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2- to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease.

Published
2010
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