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3. Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer’s disease

Author

Tallon, Carolyn, primary, Bell, Benjamin J, additional, Malvankar, Medhinee M, additional, Deme, Pragney, additional, Nogueras-Ortiz, Carlos, additional, Eren, Erden, additional, Thomas, Ajit G, additional, Hollinger, Kristen R, additional, Pal, Arindom, additional, Mustapic, Maja, additional, Huang, Meixiang, additional, Coleman, Kaleem, additional, Joe, Tawnjerae R, additional, Rais, Rana, additional, Haughey, Norman J, additional, Kapogiannis, Dimitrios, additional, and Slusher, Barbara S, additional

Published
2023
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5. Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Author

Tallon, Carolyn, primary, Bell, Benjamin J., additional, Sharma, Anjali, additional, Pal, Arindom, additional, Malvankar, Medhinee M., additional, Thomas, Ajit G., additional, Yoo, Seung-Wan, additional, Hollinger, Kristen R., additional, Coleman, Kaleem, additional, Wilkinson, Elizabeth L., additional, Kannan, Sujatha, additional, Haughey, Norman J., additional, Kannan, Rangaramanujam M., additional, Rais, Rana, additional, and Slusher, Barbara S., additional

Published
2022
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7. Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Author

Zhu, Xiaolei, primary, Hollinger, Kristen R., additional, Huang, Yiyao, additional, Borjabad, Alejandra, additional, Kim, Boe-Hyun, additional, Arab, Tanina, additional, Thomas, Ajit G., additional, Moniruzzaman, Mohammed, additional, Lovell, Lyndah, additional, Turchinovich, Andrey, additional, Witwer, Kenneth W., additional, Volsky, David J., additional, Haughey, Norman J., additional, and Slusher, Barbara S., additional

Published
2022
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9. Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis

Author

Hollinger, Kristen R., primary, Sharma, Anjali, additional, Tallon, Carolyn, additional, Lovell, Lyndah, additional, Thomas, Ajit G., additional, Zhu, Xiaolei, additional, Wiseman, Robyn, additional, Wu, Ying, additional, Kambhampati, Siva P., additional, Liaw, Kevin, additional, Sharma, Rishi, additional, Rojas, Camilo, additional, Rais, Rana, additional, Kannan, Sujatha, additional, Kannan, Rangaramanujam M., additional, and Slusher, Barbara S., additional

Published
2022
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11. Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice

Author

Hollinger, Kristen R., primary, Zhu, Xiaolei, additional, Khoury, Elizabeth S., additional, Thomas, Ajit G., additional, Liaw, Kevin, additional, Tallon, Carolyn, additional, Wu, Ying, additional, Prchalova, Eva, additional, Kamiya, Atsushi, additional, Rojas, Camilo, additional, Kannan, Sujatha, additional, and Slusher, Barbara S., additional

Published
2020
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12. Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer’s Disease

Author

Šála, Michal, primary, Hollinger, Kristen R., additional, Thomas, Ajit G., additional, Dash, Ranjeet P., additional, Tallon, Carolyn, additional, Veeravalli, Vijayabhaskar, additional, Lovell, Lyndah, additional, Kögler, Martin, additional, Hřebabecký, Hubert, additional, Procházková, Eliška, additional, Nešuta, Ondřej, additional, Donoghue, Amanda, additional, Lam, Jenny, additional, Rais, Rana, additional, Rojas, Camilo, additional, Slusher, Barbara S., additional, and Nencka, Radim, additional

Published
2020
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14. Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Author

Nedelcovych, Michael, Dash, Ranjeet P., Tenora, Lukáš, Zimmermann, Sarah C., Gadiano, Alexandra J., Garrett, Caroline, Alt, Jesse, Hollinger, Kristen R., Pommier, Elie, Jančařík, Andrej, Rojas, Camilo, Thomas, Ajit G., Wu, Ying, Wozniak, Krystyna, Majer, Pavel, Slusher, Barbara S., and Rais, Rana

Abstract

2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1resulted in similar plasma exposure of 2-PMPA versus the IN route (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 99 ± 24 h·nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.

Published
2024
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15. Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Author

Nedelcovych, Michael, primary, Dash, Ranjeet P., additional, Tenora, Lukáš, additional, Zimmermann, Sarah C., additional, Gadiano, Alexandra J., additional, Garrett, Caroline, additional, Alt, Jesse, additional, Hollinger, Kristen R., additional, Pommier, Elie, additional, Jančařík, Andrej, additional, Rojas, Camilo, additional, Thomas, Ajit G., additional, Wu, Ying, additional, Wozniak, Krystyna, additional, Majer, Pavel, additional, Slusher, Barbara S., additional, and Rais, Rana, additional

Published
2017
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19. Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer's disease.

Author

Tallon C, Bell BJ, Malvankar MM, Deme P, Nogueras-Ortiz C, Eren E, Thomas AG, Hollinger KR, Pal A, Mustapic M, Huang M, Coleman K, Joe TR, Rais R, Haughey NJ, Kapogiannis D, and Slusher BS

Abstract

Background: Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity., Methods: To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in brain ceramide and sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of brain-derived EVs in plasma and their Tau content. Additionally, we evaluated the ability of PDDC to impede tau propagation in a murine model where an adeno-associated virus(AAV) encoding for P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus and the contralateral transfer to the dentate gyrus was monitored., Results: Similar to human AD, PS19 mice exhibited increased brain ceramides and nSMase2 activity; both were completely normalized by PDDC treatment. PS19 mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all pathologic features of human AD. PDDC treatment significantly attenuated these aberrant changes. Mouse plasma isolated from PDDC-treated PS19 mice exhibited reduced levels of neuron- and microglia-derived EVs, the former carrying lower phosphorylated Tau(pTau) levels, compared to untreated mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly decreased tau spreading to the contralateral side., Conclusions: PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD mice., Competing Interests: Competing interests: C.T., A.G.T., R.R., and N.J.H and B.S.S. are listed as inventors in patent applications filed by Johns Hopkins Technology Ventures covering novel compositions and utilities of nSMase2 inhibitors, including PDDC. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. Other authors declare that no conflict of interest exist.

Published
2023
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20. FOLH1 /GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities.

Author

Rais R, Jiang W, Zhai H, Wozniak KM, Stathis M, Hollinger KR, Thomas AG, Rojas C, Vornov JJ, Marohn M, Li X, and Slusher BS

Abstract

Recent gene-profiling analyses showed significant upregulation of the folate hydrolase ( FOLH1 ) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent FOLH1 / GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC 50 = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in FOLH1 -/- mice who exhibited resistance to DSS treatment. In the murine IL-10 -/- model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of FOLH1 /GCPII enzymatic inhibition as a therapeutic option for IBD.

Published
2016
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