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5 results on '"Leticia M Toledo-Sherman"'

1. The therapeutic landscape of tauopathies: challenges and prospects

Author

Jeffrey L. Cummings, M. Isabel Gonzalez, Martyn C. Pritchard, Patrick C. May, Leticia M. Toledo-Sherman, and Glenn A. Harris

Subjects
Alzheimer’s disease, Drug development, Frontotemporal dementia, Progressive supranuclear palsy, Corticobasal degeneration, Chronic traumatic encephalopathy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Tauopathies are a group of neurodegenerative disorders characterized by the aggregation of the microtubule-associated protein tau. Aggregates of misfolded tau protein are believed to be implicated in neuronal death, which leads to a range of symptoms including cognitive decline, behavioral change, dementia, and motor deficits. Currently, there are no effective treatments for tauopathies. There are four clinical candidates in phase III trials and 16 in phase II trials. While no effective treatments are currently approved, there is increasing evidence to suggest that various therapeutic approaches may slow the progression of tauopathies or improve symptoms. This review outlines the landscape of therapeutic drugs (indexed through February 28, 2023) that target tau pathology and describes drug candidates in clinical development as well as those in the discovery and preclinical phases. The review also contains information on notable therapeutic programs that are inactive or that have been discontinued from development.

Published
2023
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2. Application of an in Vitro Blood–Brain Barrier Model in the Selection of Experimental Drug Candidates for the Treatment of Huntington’s Disease

Author

Mark Rose, Odalys Gonzalez Paz, Giulio Auciello, Annalise Di Marco, Todd Herbst, Ignacio Muñoz-Sanjuán, Domenico Vignone, Edith Monteagudo, Vinod Khetarpal, Matteo Zini, Maria Rosaria Battista, Laura Orsatti, Vincenzo Summa, Celia Dominguez, Leticia M Toledo-Sherman, Ivan Fini, Antonella Cellucci, Di Marco, A., Gonzalez Paz, O., Fini, I., Vignone, D., Cellucci, A., Battista, M. R., Auciello, G., Orsatti, L., Zini, M., Monteagudo, E., Khetarpal, V., Rose, M., Dominguez, C., Herbst, T., Toledo-Sherman, L., Summa, V., and Munoz-Sanjuan, I.

Subjects
Swine, Pharmaceutical Science, 02 engineering and technology, Pharmacology, efflux transporter, 030226 pharmacology & pharmacy, brain penetration, Rats, Sprague-Dawley, 0302 clinical medicine, Drug Discovery, Electric Impedance, Coculture Technique, Cells, Cultured, Cerebral Cortex, Endothelial Cell, Tight junction, Tight Junction, Drug discovery, Chemistry, Huntington's disease, Biological activity, 021001 nanoscience & nanotechnology, Huntington Disease, medicine.anatomical_structure, Blood-Brain Barrier, Molecular Medicine, Central Nervous System Agent, CNS, Astrocyte, 0210 nano-technology, ATP-Binding Cassette Transporter, Central nervous system, Blood–brain barrier, Models, Biological, Permeability, Tight Junctions, Capillary Permeability, 03 medical and health sciences, In vivo, Huntingtin Protein, medicine, Animals, Solute Carrier Protein, Solute Carrier Proteins, Animal, Endothelial Cells, medicine.disease, Coculture Techniques, Rats, Astrocytes, transport, Rat, ATP-Binding Cassette Transporters, Central Nervous System Agents
Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the huntingtin protein. For drug candidates targeting HD, the ability to cross the blood-brain barrier (BBB) and reach the site of action in the central nervous system (CNS) is crucial for achieving pharmacological activity. To assess the permeability of selected compounds across the BBB, we utilized a two-dimensional model composed of primary porcine brain endothelial cells and rat astrocytes. Our objective was to use this in vitro model to rank and prioritize compounds for in vivo pharmacokinetic and brain penetration studies. The model was first characterized using a set of validation markers chosen based on their functional importance at the BBB. It was shown to fulfill the major BBB characteristics, including functional tight junctions, high transendothelial electrical resistance, expression, and activity of influx and efflux transporters. The in vitro permeability of 54 structurally diverse known compounds was determined and shown to have a good correlation with the in situ brain perfusion data in rodents. We used this model to investigate the BBB permeability of a series of new HD compounds from different chemical classes, and we found a good correlation with in vivo brain permeation, demonstrating the usefulness of the in vitro model for optimizing CNS drug properties and for guiding the selection of lead compounds in a drug discovery setting. ©

Published
2019
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3. Current directions in tau research: Highlights from Tau 2020

Author

Keith A. Johnson, Michael Gold, Yakeel T. Quiroz, Sarah L. DeVos, Howard Feldman, Bradley T. Hyman, Susan Worley, Heather M. Snyder, Adam L. Boxer, Gil D. Rabinovici, Luc Buée, Pat Brannelly, Catherine J. Mummery, Irene Litvan, Leticia M Toledo-Sherman, James Mutamba, Kristin R. Wildsmith, Marc C. Patterson, Celeste M. Karch, Dirk Beher, Jean Pierre Brion, Maria C. Carrillo, Claire Sexton, Gaël Chételat, Martin Citron, Huw R. Morris, Alison Goate, Kristophe Diaz, Stacie Weninger, Amy Rommel, Diana R. Kerwin, Angela Cacace, Melanie B Shulman, Walter J. Koroshetz, Bess Frost, Alzheimer's Association, Asceneuron [Lausanne, Switzerland], University of California [San Francisco] (UC San Francisco), University of California (UC), Alzheimer's Disease Data Initiative [Kirkland, WI, USA] (ADDI), Université libre de Bruxelles (ULB), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuroscience and Platform Biology [Arvinas, NH, USA] (NPB), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Blood and Brain @ Caen-Normandie [Caen] (BB@C), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCB Biopharma [Brussels, Belgium] (UCB-B), Denali Therapeutics [San Francisco, CA, USA]. (DT), Cure PSP [New York, NY, USA] (C-PSP), University of California [San Diego] (UC San Diego), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Abbvie Inc. [North Chicago], Harvard Medical School [Boston] (HMS), Department of radiology (Massachusetts General Hospital), Massachusetts General Hospital [Boston], Washington University in Saint Louis (WUSTL), University of Texas Southwestern Medical Center [Dallas], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), UCL Institute of Neurology, Queen Square [London], University College of London [London] (UCL), Longwood Fund [Boston, MA, USA] (LF), Mayo Clinic [Rochester], Rainwater Charitable Foundation [Fort Worth, TX, USA] (RCF), Biogen [Boston, MA, USA], F-Prime Capital [Cambridge, MA, USA] (FBRI), Genentech, Inc. [San Francisco], Independent science writer [Bryn Mawr, PA, USA] (ISW), University of California [San Francisco] (UCSF), University of California, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), University of Texas Health Science Center at San Antonio [San Antonio], Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), and BUEE, Luc

Subjects
Aging, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Sciences, tau Proteins, Neurodegenerative, Alzheimer's Disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, Neurologie, Political science, Drug Discovery, Acquired Cognitive Impairment, therapeutics, Humans, Cognitive Dysfunction, tau, Cognitive decline, 030304 developmental biology, Pace, 0303 health sciences, Government, business.industry, Health Policy, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurosciences, neurodegeneration, Médecine pathologie humaine, biomarkers, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neuropathologie, Sciences bio-médicales et agricoles, Public relations, Alzheimer's, 3. Good health, Brain Disorders, Psychiatry and Mental health, Geriatrics, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research., info:eu-repo/semantics/published

Published
2021
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4. High-throughput virtual screening for drug discovery in parallel

Author

Leticia M, Toledo-Sherman and Deqi, Chen

Subjects
Structure-Activity Relationship, Binding Sites, Drug Delivery Systems, Drug Design, Animals, Combinatorial Chemistry Techniques, Humans
Abstract

With the influx of targets generated by genomics and proteomics initiatives, a new drug discovery paradigm is emerging. Many companies are setting up target family platforms that tackle multiple targets and therapeutic areas simultaneously. Virtual screening (VS) techniques are a fundamental component of such platforms for in silico filtering of compound collections and prioritization of chemistry and screening efforts. At the heart of these, structure-based docking and scoring methods are especially effective in identifying bioactive molecules if the structure of a target is available. As structural genomics maps the structural space of the proteome, these techniques are expected to become commonplace. In light of this, an overview of the latest developments in VS methodology is given here. In particular, emphasis is placed on those techniques adaptable to high-throughput VS in parallel drug discovery platforms. The first examples of docking across multiple targets have already appeared in the literature and will be reviewed here.

Published
2002

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