Alzheimers Drug Discovery Foundation

New York City, NY, United States

Alzheimers Drug Discovery Foundation

New York City, NY, United States
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Lane R.F.,Mount Sinai School of Medicine | Lane R.F.,AlzheimerS Drug Discovery Foundation | Steele J.W.,Mount Sinai School of Medicine | Steele J.W.,Rockefeller University | And 5 more authors.
Journal of Neuroscience | Year: 2013

Endosomal sorting of the Alzheimer amyloid precursor protein (APP) plays a key role in the biogenesis of the amyloid-β (Aβ) peptide. Genetic lesions underlying Alzheimer's disease (AD) can act by interfering with this physiological process. Specifically, proteins involved in trafficking between endosomal compartments and the trans-Golgi network (TGN) [including the retromer complex (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1)] have been implicated in the molecular pathology of late-onset AD. Previously, we demonstrated a role for SorCS1 in APP metabolism and Aβ production and, while we implicated a role for the retromer in this regulation, the underlying mechanism remained poorly understood. Here, we provide evidence for a motif within the SorCS1c cytoplasmic tail that, when manipulated, results in perturbed sorting of APP and/or its fragments to endosomal compartments, decreased retrograde TGN trafficking, and increased Aβ production in H4 neuroglioma cells. These perturbations apparently do not involve turnover of the cell surface APP pool, but rather they involve intracellular APP and/or its fragments, downstream of APP endocytosis. © 2013 the authors.

Lane R.F.,Alzheimers Drug Discovery Foundation | St George-Hyslop P.,University of Toronto | St George-Hyslop P.,University of Cambridge | Hempstead B.L.,New York Medical College | And 4 more authors.
Journal of Neuroscience | Year: 2012

Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to the trans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neurotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration. © 2012 the authors.

Rance N.E.,University of Arizona | Dacks P.A.,University of Arizona | Dacks P.A.,Alzheimers Drug Discovery Foundation | Mittelman-Smith M.A.,University of Arizona | And 2 more authors.
Frontiers in Neuroendocrinology | Year: 2013

Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK3R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes. © 2013.

Lin P.-J.,Institute for Clinical Research and Health Policy Studies | Fillit H.M.,Alzheimers Drug Discovery Foundation | Cohen J.T.,Institute for Clinical Research and Health Policy Studies | Neumann P.J.,Institute for Clinical Research and Health Policy Studies
Alzheimer's and Dementia | Year: 2013

Background: Individuals with Alzheimer's disease and related disorders (ADRD) have more frequent hospitalizations than individuals without ADRD, and some of these admissions may be preventable with proactive outpatient care. Methods: This study was a cross-sectional analysis of Medicare claims data from 195,024 fee-for-service ADRD beneficiaries aged ≥65 years and an equal number of matched non-ADRD controls drawn from the 5% random sample of Medicare beneficiaries in 2007-2008. We analyzed the proportion of patients with potentially avoidable hospitalizations (PAHs, as defined by the Medicare Ambulatory Care Indicators for the Elderly) and used logistic regression to examine patient characteristics associated with PAHs. We used paired t tests to compare Medicare expenditures by ADRD status, stratified by whether there were PAHs related to a particular condition. Results: Compared with matched non-ADRD subjects, Medicare beneficiaries with ADRD were significantly more likely to have PAHs for diabetes short-term complications (OR = 1.43; 95% CI 1.31-1.57), diabetes long-term complications (OR = 1.08; 95% CI = 1.02-1.14), and hypertension (OR = 1.22; 95% CI 1.08-1.38), but less likely to have PAHs for chronic obstructive pulmonary disease (COPD)/asthma (OR = 0.85; 95% CI 0.82-0.87) and heart failure (OR = 0.89; 95% CI 0.86-0.92). Risks of PAHs increased significantly with comorbidity burden. Among beneficiaries with a PAH, total Medicare expenditures were significantly higher for those subjects who also had ADRD. Conclusion: Medicare beneficiaries with ADRD were at a higher risk of PAHs for certain uncontrolled comorbidities and incurred higher Medicare expenditures compared with matched controls without dementia. ADRD appears to make the management of some comorbidities more difficult and expensive. Ideally, ADRD programs should involve care management targeting high-risk patients with multiple chronic conditions. © 2013 The Alzheimer's Association. All rights reserved.

News Article | November 7, 2016

A new step in the collaboration to fight Alzheimer's Disease BARCELONA, SPAIN and CAMBRIDGE, MA--(Marketwired - November 07, 2016) - Oryzon Genomics ( : ORY) (ISIN Code: ES0167733015, ORY), a public clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the Alzheimer's Drug Discovery Foundation (ADDF) exercised warrants and lending rights over 175,071 ordinary shares of the Company, at an exercise price of EUR 3.43 per share (par value EUR 0.05 each) representing 0.6% of the capital. The ADDF previously awarded two grants to the Company to support the development of its molecule ORY-2001, a dual LSD1-MAOB inhibitor, as a new therapeutic approach for Alzheimer's disease (AD). The Company is now finishing a Phase I trial to evaluate the safety, tolerability and pharmacokinetics of ORY-2001 in 88 healthy subjects as well as an elderly population. With a successful study outcome, ORY-2001 is expected to proceed to a Phase II study in Alzheimer's disease patients in 1H 2017. Dr. Carlos Buesa, CEO of Oryzon, commented: "Support from the ADDF has been key for us in advancing the development of this novel therapeutic option for Alzheimer's disease, and we are very grateful. The ADDF's decision to convert the loan extended to the Company in earlier years into equity reflects its confidence in our project and the shared hope that this experimental drug may contribute to the cure of this terrible disease." Dr. Howard Fillit, Founding Executive Director and Chief Scientific Officer of the ADDF, said: "We are pleased to continue our investment in Oryzon Genomics. Its promising drug ORY-2001 has progressed rapidly into clinical study and has the potential to become the first epigenetic therapy for a neurodegenerative disease." ORY-2001 is a highly selective dual oral LSD1-MAOB inhibitor. The molecule, which focuses on cognitive decline and memory loss, it is brain penetrant and has a good safety profile and therapeutic index in preclinical trials. In nontransgenic AD mouse models, long-term treatments with the drug demonstrated a marked cognitive improvement. The product is currently in Phase I clinical study in healthy volunteers. The company is also exploring its potential in other CNS disorders like Multiple Sclerosis and Huntington Disease. Founded in 1998 by Leonard A. and Ronald S. Lauder, the Alzheimer's Drug Discovery Foundation (ADDF) is dedicated to rapidly accelerating the discovery of drugs to prevent, treat and cure Alzheimer's disease. The ADDF is the only public charity solely focused on funding the development of drugs for Alzheimer's, employing a venture philanthropy model to support research in academia and the biotech industry. Through the generosity of its donors, the ADDF has awarded nearly $100 million to fund more than 500 Alzheimer's drug discovery programs and clinical trials in 18 countries. To learn more, please visit: Alzheimer's disease is the most common form of dementia in adults. It is estimated to affect 5.3 million Americans and over 30 million people worldwide with an average course of 8-12 years. It is projected that the disease prevalence will double over the next 20 years. Marketed products address some of the symptoms, but there are no treatments currently available. The economic cost of Alzheimer's is expected to grow in the coming years. Projections of the direct cost of Alzheimer's disease in adults over 65 could balloon to $1.1 trillion in 2050 (in today's dollars) with a total of $20.8 trillion in medical costs between 2015 and 2050, according to the Alzheimer's Association. Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company considered as the European champion in Epigenetics. The company has one of the strongest portfolios in the field and a clinical asset already partnered with Roche. Oryzon's LSD1 program is currently covered by +20 patent families and has rendered two compounds in clinical trials. In addition, Oryzon has ongoing programs for developing inhibitors against other epigenetic targets. The company has a strong technological platform for biomarker identification and performs biomarker and target validation for a variety of malignant and neurodegenerative diseases. Oryzon's strategy is to develop first in class compounds against novel epigenetic targets through Phase II clinical trials, at which point it is decided on a case-by-case basis to either keep the development in-house or to partner or outlicense the compound for late stage development and commercialization. The company has offices in Barcelona and Cambridge, Massachusetts. For more information, visit This communication contains forward-looking information and statements about Oryzon Genomics, S.A., including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words "expects", "anticipates", "believes", "intends", "estimates" and similar expressions. Although Oryzon Genomics, S.A. believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon Genomics, S.A. shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon Genomics, S.A., that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon Genomics, S.A. to the Comisión Nacional del Mercado de Valores, which are accessible to the public. Forward-looking statements are not guarantees of future performance. The auditors of Oryzon Genomics, S.A, have not reviewed them. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon Genomics, S.A. or any of its members, directors, officers, employees or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon Genomics, S.A. on the date hereof. Except as required by applicable law, Oryzon Genomics, S.A. does not undertake any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

Lane R.F.,Alzheimers Drug Discovery Foundation | Shineman D.W.,Alzheimers Drug Discovery Foundation | Steele J.W.,Rockefeller University | Lee L.B.H.,Columbia University | Fillit H.M.,Alzheimers Drug Discovery Foundation
Advances in Pharmacology | Year: 2012

Currently, the field is awaiting the results of several pivotal Phase III clinical Alzheimer's disease (AD) trials that target amyloid-β (Aβ). In light of the recent biomarker studies that indicate Aβ levels are at their most dynamic 5-10 years before the onset of clinical symptoms, it is becoming uncertain whether direct approaches to target Aβ will achieve desired clinical efficacy. AD is a complex neurodegenerative disease caused by dysregulation of numerous neurobiological networks and cellular functions, resulting in synaptic loss, neuronal loss, and ultimately impaired memory. While it is clear that Aβ plays a key role in the pathogenesis of AD, it may be a challenging and inefficient target for mid-to-late stage AD intervention. Throughout the course of AD, multiple pathways become perturbed, presenting a multitude of possible therapeutic avenues for design of AD intervention and prophylactic therapies. In this chapter, we sought to first provide an overview of Aβ-directed strategies that are currently in development, and the pivotal Aβ-targeted trials that are currently underway. Next, we delve into the biology and therapeutic designs associated with other key areas of research in the field including tau, protein trafficking and degradation pathways, ApoE, synaptic function, neurotrophic/neuroprotective strategies, and inflammation and energy utilization. For each area we have provided a comprehensive and balanced overview of the therapeutic strategies currently in preclinical and clinical development, which will shape the future therapeutic landscape of AD. © 2012 Elsevier Inc.

Dacks P.A.,Mount Sinai School of Medicine | Dacks P.A.,Alzheimers Drug Discovery Foundation | Moreno C.L.,Mount Sinai School of Medicine | Kim E.S.,Mount Sinai School of Medicine | And 2 more authors.
Frontiers in Neuroendocrinology | Year: 2013

Dietary restriction (DR) can extend lifespan and reduce disease burden across a wide range of animals and yeast but the mechanisms mediating these remarkably protective effects remain to be elucidated despite extensive efforts. Although it has generally been assumed that protective effects of DR are cell-autonomous, there is considerable evidence that many whole-body responses to nutritional state, including DR, are regulated by nutrient-sensing neurons. In this review, we explore the hypothesis that nutrient sensing neurons in the ventromedial hypothalamus hierarchically regulate the protective responses of dietary restriction. We describe multiple peripheral responses that are hierarchically regulated by the hypothalamus and we present evidence for non-cell autonomous signaling of dietary restriction gathered from a diverse range of models including invertebrates, mammalian cell culture, and rodent studies. © 2012 Elsevier Inc.

Lane R.F.,Alzheimers Drug Discovery Foundation | Shineman D.W.,Alzheimers Drug Discovery Foundation | Fillit H.M.,Alzheimers Drug Discovery Foundation
Alzheimer's Research and Therapy | Year: 2011

Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 © 2011 BioMed Central Ltd.

Carman A.J.,Alzheimers Drug Discovery Foundation | Dacks P.A.,Alzheimers Drug Discovery Foundation | Lane R.F.,Alzheimers Drug Discovery Foundation | Shineman D.W.,Alzheimers Drug Discovery Foundation | Fillit H.M.,Alzheimers Drug Discovery Foundation
Journal of Nutrition, Health and Aging | Year: 2014

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

Dacks P.A.,Alzheimers Drug Discovery Foundation | Shineman D.W.,Alzheimers Drug Discovery Foundation | Fillit H.M.,Alzheimers Drug Discovery Foundation
Journal of Nutrition, Health and Aging | Year: 2013

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE É 4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs. © 2012 Serdi and Springer-Verlag France.

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