PubMed | Rockefeller University, Oligomerix, Inc, University of Toronto, Catholic University of the Sacred Heart and 5 more.
Type: | Journal: Scientific reports | Year: 2016
Non-fibrillar soluble oligomeric forms of amyloid- peptide (oA) and tau proteins are likely to play a major role in Alzheimers disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oA initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of A, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oA levels. The impairment is immediate as it raises as soon as 20min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oA to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and A on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with A and tau pathology.
Tian H.,Arizona State University |
Davidowitz E.,Oligomerix, Inc |
Lopez P.,Oligomerix, Inc |
He P.,Arizona State University |
And 3 more authors.
Neurobiology of Aging | Year: 2015
Oligomeric tau species are important in the onset and progression of Alzheimer's disease (AD), as they are neurotoxic and can propagate tau-tangle pathology. Therefore, reagents that selectively recognize different key morphologies of tau are needed to help define the role of tau in AD and related diseases. We utilized a biopanning protocol that combines the binding diversity of phage-displayed antibody libraries with the powerful imaging capability of atomic force microscopy to isolate single-chain antibody fragments (scFvs) that selectively bind toxic oligomeric tau. We isolated 3 different antibody fragments that bind oligomeric but not monomeric or fibrillar tau. The scFvs differentiate brain tissue homogenates of both 3×TG and tau-AD mice from wild-type mice, detecting oligomeric tau at much earlier ages than when neurofibrillary tangles are typically detected. The scFvs also distinguish human postmortem AD brain tissue from cognitively normal postmortem human brain tissue, demonstrating the potential of this approach for developing biomarkers for early detection and progression of AD. © 2015 Elsevier Inc.
Tian H.,Arizona State University |
Davidowitz E.,Oligomerix, Inc |
Lopez P.,Oligomerix, Inc |
Emadi S.,Arizona State University |
And 2 more authors.
International Journal of Cell Biology | Year: 2013
In Alzheimer's disease (AD), tau aggregates into fibrils and higher order neurofibrillary tangles, a key histopathological feature of AD. However, soluble oligomeric tau species may play a more critical role in AD progression since these tau species correlate better with neuronal loss and cognitive dysfunction. Recent studies show that extracellular oligomeric tau can inhibit memory formation and synaptic function and also transmit pathology to neighboring neurons. However, the specific forms of oligomeric tau involved in toxicity are still unknown. Here, we used two splice variants of recombinant human tau and generated monomeric, dimeric, and trimeric fractions of each isoform. The composition of each fraction was verified chromatographically and also by atomic force microscopy. The toxicity of each fraction toward both human neuroblastoma cells and cholinergic-like neurons was assessed. Trimeric, but not monomeric or dimeric, tau oligomers of both splice variants were neurotoxic at low nanomolar concentrations. Further characterization of tau oligomer species with disease-specific modifications and morphologies is necessary to identify the best targets for the development of biomarker and therapeutic development for AD and related tauopathies. © 2013 Huilai Tian et al.
Gao Z.,Sanofi S.A. |
Hurst W.J.,Sanofi S.A. |
Czechtizky W.,Sanofi S.A. |
Francon D.,Sanofi S.A. |
And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), Ki = 8.6 nM, rhesus monkey (rh-H3R), Ki = 1.2 nM, and rat (r-H3R), Ki = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders. © 2013 Elsevier Ltd. All rights reserved.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 749.79K | Year: 2016
DESCRIPTION provided by applicant The prevalence of Alzheimerandapos s disease AD is increasing worldwide due to demographic shifts resulting from an aging population It is the most costly disease in the US with a financial burden of over $ billion annually in direct costs that are estimated to increase to $ trillion by Disease modifying drugs that change the clinical course and delay symptomatic progression could reduce the economic burden by multiples of tens of billions of dollars per year if the onset of AD is delayed even a few years To date all completed phase clinical studies based on the amyloid hypothesis have failed to meet their clinical endpoints underscoring the critical need for alternative approaches for the development of AD therapeutics The Company is developing disease modifying small molecule drugs for AD that target the initial step in tau aggregation leading to the formation of tau oligomers the toxic tau aggregates responsible for neuronal loss and impairment of memory formation Competing programs use methods to select compounds inhibiting the formation of tau fibrils or large aggregates previously thought to be the most toxic tau species We hypothesized that by targeting the first step in tau self association all forms of tau aggregates should be reduced The long term goal of the project is to advance disease modifying drugs for AD to clinical studies and the market The objective of this proposal is to validate our small molecule discovery platform targeting tau oligomer formation The top candidate from our lead series of compounds will be used to demonstrate target engagement in the htau mouse model The program aims are to Select a compound from our lead series for the in vivo study Produce and formulate the selected compound for the in vivo study Demonstrate target engagement in the htau mouse model Histological and biochemical analyses will be used to assess efficacy of compound for the in vivo reduction of tau pathology Estimates show U S only sales for a disease modifying therapeutic in the first year of launch of greater than $ billion and surpassing $ billion within years post launch The commercialization strategy is to form a strategic partnership with a large pharmaceutical company to accelerate to clinical studies and to the market Significantly the Company is now negotiating a collaboration with three different large pharma companies This program will collaborate with Dr Peter Davies a major thought leader and world renowned expert in the study of tau pathology in Alzheimerandapos s disease and in whose lab the htau mouse model was developed PUBLIC HEALTH RELEVANCE In this Direct to Phase II SBIR Oligomerix plans to validate its drug discovery program using the most relevant mouse model for Alzheimerandapos s disease AD for tau aggregation This will significantly enable the Company to develop drugs for clinical studies for AD Additionally this program is being performed with the involvement of Dr Peter Davies a world expert in the tau and AD fields and in whose lab this mouse model was developed
Oligomerix, Inc | Date: 2012-05-18
Disclosed are mammalian tau proteases, as well as proteolytically-active fragments, variants, and mutants thereof. Also disclosed are polynucleotides and recombinant expression vectors that encode these polypeptides, as well as methods for producing such proteins in selected recombinant host cells, and for using the compositions in a variety of diagnostic and analytical assays.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.65M | Year: 2010
DESCRIPTION (provided by applicant): High Throughput Tau Oligomer Assay for Drug Screening for Alzheimer's Disease Project Summary: There is a large and rapidly growing unmet need for disease modifying drugs for Alzheimer's disease. Currently there are 18 million cases of AD worldwide; by 2025 this number is expected to increase to 34 million. Presently, only 5 mildly effective AD symptom-treating drugs exist, but none that treat the underlying neurodegenerative processes. Tau is becoming a more prominent target for the development of disease- modifying drugs (DMDs), as its role in neurodegeneration is becoming better understood. Mutations in the gene for tau protein MAPT are causative of dementia and tau pathology correlates well with AD progression. At the same time, late stage clinical failures for therapeutics based on the amyloid hypothesis have raised questions on solely targeting A2. Strong evidence has emerged implicating tau oligomers as playing a direct role in disease pathogenesis for AD and over 20 other neurodegenerative diseases (Brunden et al. 2008; Davidowitz et al. 2008). To discover drugs targeting tau oligomerization methods were developed to select compounds inhibiting tau self-interaction, and an assay using AlphaScreen detection technology was selected for further development for high throughput screening (Chatterjee et al. 2008). In addition, the phage display- atomic force microscopy method developed by Dr. Sierks (ASU) was used to isolate antibody fragments (scFvs) specifically binding to tau oligomers that will be adopted in the cell based screening assays. The specific aims of the proposed program are as follows: Convert the tau oligomer assay to HTS format Transfer Assay to the Michigan High Throughput Screening Center (MHTSC) for automation and screening of a highly optimized compound library (100,000 compounds) and carry out medicinal chemistry analysis to model the pharmacophore and select additional chemotypes for screening Select compounds using tau oligomer specific antibody fragments in cell based assays The anticipated outcome of the proposed Phase II program is the selection of at least three or more lead candidate compounds targeting tau oligomers that will be developed during the Phase III program and evaluated in animal models of AD and tauopathies. To attain this result, the high throughput assay will be optimized and transferred to the Michigan High Throughput Screening Center where their Select Set library of approximately 100,000 compounds will be screened under the direction Dr. Robert Kilkuskie Hits will be validated and a structural pharmacaophore model will be developed. Toxic compounds will be eliminated using a neurocytotoxicity assay. Three or more scFvs will be selected with high sensitivity and specificity that will be used to identify compounds inhibiting tau self-association using in vitro cell based assays. Antibody fragments, in addition to enabling the primary goal, are supportive of the company's other programs including its tau biomarker development program and its tau immunotherapeutic program. However, the primary goal of the program is to advance the tau oligomer drug discovery platform to identify active inhibitors as lead candidates for IND enabling studies. Key Words Alzheimer's disease, tauopathy, neurodegenerative disease, drug discovery, tau oligomer, phage display, antibody fragment, scFv, high throughput screening PUBLIC HEALTH RELEVANCE: The proposed program focuses on developing a high throughput screening assay targeting tau oligomers for drug discovery for Alzheimer's disease (AD). This project was inspired by observations that accumulation of tau oligomers has been shown to correlate well with neuronal loss and memory impairment in AD and in tauopathy mouse models. OLIGOMERIX has developed in vitro assays for screening compounds that inhibit the formation of cytotoxic tau oligomers. This program aims to 1.) .Convert the tau oligomer assay to HTS format; 2.) Transfer Assay to the Michigan High Throughput Screening Center (MHTSC) for automation and screening of a highly optimized compound library (100,000 compounds) and carry out medicinal chemistry analysis to model the pharmacophore; 3.) Select compounds using tau oligomer specific antibody fragments and cell based screening to identify lead candidates for future animal studies and pre-clinical development.
Oligomerix, Inc | Date: 2016-10-04
Tau protein has a causative role in Alzheimers disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. Here, novel compositions of tau oligomers and novel mechanisms for tau oligomer nucleation, extension and termination are taught. Methods for producing and purifying these structures for the development of small molecule and immunotherapeutics as well as antibodies for biomarkers of neurodegenerative diseases are taught.
Oligomerix, Inc | Date: 2013-03-26
Chemical products and compositions intended for medical research, namely, reagents, chemical entities and compounds; chemical preparations for scientific purposes, chemical reagents or products for laboratory analyses for monitoring, analyzing and identifying diagnostic targets and therapeutic products, and for conducting research in connection with pharmaceutical sciences; chemical preparations intended for scientific purposes, namely, for leading research in connection with pharmaceutical sciences. Pharmaceutical products for the treatment of diseases, namely, Alzheimers disease and other neurodegenerative diseases; reagents for diagnostic purposes and diagnostic media intended for medical purposes, namely, reagents and media intended for tests, namely, tests based on blood biomarkers for identifying patients affected by diseases or those at risk of developing a disease and for identifying patients responding to specific personalized treatments; biological acidic products and preparations for pharmaceutical purposes, namely, pharmaceutical preparations for diagnosing diseases, namely, Alzheimers disease and other neurodegenerative diseases; chemico-pharmaceutical preparations for diagnosing, preventing and treating diseases, namely, Alzheimers disease and other neurodegenerative diseases; biopharmaceutical products, namely, reagents, chemical entities and compounds for diagnosing, preventing and treating diseases, namely, Alzheimers disease and other neurodegenerative diseases; chemical preparations for medical and pharmaceutical purposes, namely, chemicals for diagnosing Alzheimers disease and other neurodegenerative diseases, especially chemical preparations for diagnosing diseases in the nature of neurodegenerative diseases. Research and development of pharmaceutical molecules, compounds, inhibitors, antibodies and biological markers for diagnostic purposes and medicines for treating diseases; research and development of new products and preparations for the treatment of Alzheimers disease and other neurodegenerative diseases; research and development in the field of pharmaceutical drugs; biological research; biotechnological research; technical research in the field of biotechnology; consultancy in the field of biotechnology.