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Mei F.,University of California at San Francisco | Mei F.,Chongqing Medical University | Mayoral S.R.,University of California at San Francisco | Nobuta H.,Howard Hughes Medical Institute | And 9 more authors.
Journal of Neuroscience | Year: 2016

Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of -opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (=)U-50488 compound proved to be most effective for differentiation. (=)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (=)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (=)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (=)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy. © 2016 the authors.

Powell D.A.,Inception Sciences
Expert Opinion on Therapeutic Patents | Year: 2014

Introduction: Stearoyl coenzyme-A desaturase (SCD) is a critical lipogenic enzyme that converts a range of unsaturated lipids to their corresponding monounsaturated fatty acids. Genetic and enzyme-knockdown experiments have suggested an important role of SCD1 in the regulation of various metabolic disorders. With the prognostication that SCD-inhibition may serve to remediate various metabolic diseases, several pharmaceutical companies have embarked on the development of small-molecule SCD-inhibitors, with over 100 patent applications by 17 companies being reported to date. Areas covered: Recent progress on the development of SCD-inhibitors, including preclinical efficacy and safety are reviewed. Strategies toward overcoming systemic adverse events and the establishment of a suitable therapeutic margin for clinical studies are discussed. Expert opinion: Preclinically, SCD-inhibition leads to reductions in body-weight gain, improvements in glucose clearance and improved liver-lipid profile. However, chronic SCD inhibition in skin and eye-lubricating glands results in undesirable adverse events. Several strategies to overcome these findings have been described, including alternative administration routes for acne or oncology applications, use of potent and rapidly cleared compounds and SCD-inhibitors with a liver-targeted tissue distribution profile. The attainment of sufficient therapeutic margin and robust efficacy for therapeutic applications in humans remains a major frontier for SCD-inhibitors. © 2014 Informa UK, Ltd.

Shih V.F.-S.,Genentech | Cox J.,Genentech | Cox J.,Inception Sciences | Kljavin N.M.,Genentech | And 8 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Mammalian hosts are colonized with commensal microbes in various mucosal and epithelial tissues, including the intestinal tract. In mice, the presence of segmented filamentous bacteria (SFB) promotes Th17 differentiation and the development of autoimmune disease. Here, we demonstrate that the IL-23 pathway dynamically regulates the abundance of SFB as well as mucosal barrier function in the adult animal. Genetic or pharmacological inactivation of the pathway selectively perturbs the abundance of a small group of commensals, including SFB, and results in an impaired mucosal barrier. Defective barrier function leads to systemic dissemination of microbial products, provoking induction of the IL-23 pathway with dual consequences: IL-23 drives IL-22 production to reinforce mucosal barrier function and elicit antimicrobial activities, and it also drives the differentiation of Th17 cells in an attempt to combat escaped microbesinthe lamina propriaand in distal tissues. Thus, barrier defects generate a systemic environment that facilitates Th17 development.

News Article | October 6, 2016

Using a mouse model of multiple sclerosis (MS), a research team led by UC San Francisco scientists has demonstrated for the first time that regenerating myelin – the fatty insulating sheath surrounding neural fibers that is destroyed in the disorder – can both protect neurons from damage and restore lost function. “The key thing we learned from this study is that if we can design therapies that promote remyelination – especially when myelin has been damaged by inflammation as it is in MS – we can prevent neuronal loss and restore function,” said UCSF’s Jonah R. Chan, Ph.D., the senior author of the new study, which was published September 27, 2016 in the open-access journal eLife. “This is something I and other investigators have wanted to promise to MS patients, but we simply didn’t have the data.” In MS, the immune system somehow goes awry and attacks myelin, compromising the efficient transmission of electrical impulses among brain cells. This leads to a range of progressively worsening symptoms, including vision problems, numbness, weakness, and difficulty walking. There is increasing evidence that, in addition to its insulating properties, myelin also provides metabolic support to axons, the wire-like nerve-cell extensions it ensheathes. In MS, as myelin continually degrades, axons also degenerate, ultimately causing nerve cells to die off completely. It is this degeneration that is thought to be responsible for the chronic disability and progression of symptoms seen in MS. In light of this disease process, it would seem logical that restoring myelin would protect axons, which in turn would protect neurons overall and help to maintain normal brain function, and many scientists and pharmaceutical firms are pursuing MS treatments based on just that premise. But Chan, the Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF, said he was frankly surprised to learn that there were no hard data to support this key hypothesis, and he therefore assembled an international team of scientists to conduct the new study. The researchers used the so-called EAE (experimental autoimmune encephalomyelitis) model of MS, in which mice are injected with a protein found in myelin, which incites an inflammatory autoimmune response with physiological and behavioral consequences similar to those seen in human MS. In previous UCSF research employing high-throughput drug-screening technology that Chan designed, he and colleagues discovered a cluster of compounds, all of which target proteins known as muscarinic receptors, that promote remyelination – the process by which cells known as oligodendrocytes will rewrap themselves around axons to repair the myelin sheath. Within this collection was an over-the-counter antihistamine called clemastine. In the current study, the researchers simultaneously injected mice with both clemastine and the protein that induces EAE, and they indeed found that these mice had less severe MS-like symptoms, and that some remyelination took place in the brain and spinal cord. Axons also appeared to be protected from degeneration in mice that received clemastine. But clemastine’s mechanism of action is poorly understood, Chan said, and pharmacologically speaking it is a “dirty” compound: in addition to its effects on histamine and muscarinic receptors, it interacts with many other types of receptors, and it affects many types of cells besides oligodendrocytes. So it wasn’t possible for the researchers to disentangle whether the less-severe symptoms and evidence of new myelin seen in clemastine-treated mice were truly the direct result of a specific effect of the drug on oligodendrocytes, or was instead due to some broader, indirect effect, such as dampening the overall inflammatory response. To address this question, the team conducted a series of experiments to identify which oligodendrocyte receptor clemastine might be acting on. They obtained numerous “knockout” mice, each lacking a specific receptor target, and systematically tested the drugs identified in the previous high-throughput screen in these mice. Ultimately, the team identified M1R (muscarinic acetylcholine receptor 1 subtype) as the target for clemastine and other anti-muscarinic compounds identified in the original screen, and determined that M1R was a potent inhibitor of oligodendrocyte differentiation from precursor cells, which is critical for remyelination. No drugs exist that specifically and potently block M1 without affecting other muscarinic receptors, so the group continued using a genetic approach, employing knockout mice lacking the M1 receptor specifically in oligodendrocytes and testing these mice in the EAE model of MS. In these mice, there was significant remyelination, axons were protected from degeneration, and function was restored, even when EAE inflammation was at its peak. Because of the precision of the gene knockout, the researchers are confident that all these effects followed from the absence of the M1 receptor in oligodendrocytes, which appears to have a profound inhibitory effect on remyelination. The next step, Chan said, will be to try to design a “first-in-class” M1-blocking drug and to test its efficacy in animal models, and ultimately in MS patients. To that end, Chan and co-author Ari J. Green, M.D., associate professor of neurology and clinical director of the UCSF Multiple Sclerosis Center, have partnered with Daniel Lorrain, Ph.D., head of biology, and Brian Stearns, Ph.D., head of chemistry, at San Diego-based Inception Sciences to advance this project. They were joined by researchers from the Third Military Medical University; Inception Sciences; the University of Vermont; the National Institutes of Health (NIH); and Texas Tech University Health Sciences Center. The work was funded by the National Multiple Sclerosis Society; Target ALS; The National Institutes of Health; and the Rachleff Endowment. “Now that we’ve shown we can promote repair during the peak inflammation period, and that new myelin may remain stable,” Chan said, “we can now say to MS patients that focusing on this remyelination space has the potential to not only restore function, but to improve their quality of life.”

TORONTO & MONTREAL & VANCOUVER, British Columbia--(BUSINESS WIRE)--Versant Ventures today announced that Toronto-based portfolio company Northern Biologics Inc. has executed a transformational deal that expands its pipeline and financial resources. The merger of Mosaic Biomedicals SL with Northern creates a global oncology company backed by Versant and Celgene Corp. (NASDAQ:CELG) that will advance a promising first-in-class antibody into clinical trials in 2017. This announcement also marks the fifth major investment by Versant in life science companies with Canadian operations. It closely follows last week’s debut of BlueRock Therapeutics, a stem cell company that Versant and Bayer AG jointly launched with a series A commitment of CAD$295 million, the largest ever for a Canadian life science startup. Both Northern and BlueRock are examples of harnessing top-tier science and building sustainable companies with the necessary intellectual and financial resources to bring new medicines to patients. In 2013, Versant undertook the challenge of expanding its global footprint and building a significant presence in Canada. The firm’s goal was to source the country’s best scientific opportunities and to manage those startups into successful global companies. “Since launching investment activities in Canada three years ago, our progress toward building a world-class biotech portfolio has exceeded any of our expectations,” said Brad Bolzon, Ph.D., Versant managing director. “It is a testament to the quality of the Canadian academic research community and the commitment of key stakeholders in government and the private sector to build a viable biotech ecosystem that can compete with all other global players.” Versant’s recent activity in Canada also includes portfolio company Turnstone Biologics Inc., which completed one of the largest-ever series B rounds for a Canadian biotech in November. The financing will allow Turnstone to complete ongoing clinical trials of its lead oncolytic immunotherapeutic and also launch three additional clinical programs in the coming 24 months. Like BlueRock and Northern, Turnstone’s foundation was built on scientific discoveries and new technologies developed at Canadian academic institutions. Collectively these institutions include UHN and its affiliates the McEwen Centre for Regenerative Medicine and Princess Margaret Cancer Centre, as well as the Children’s Hospital of Eastern Ontario (CHEO), McMaster University, Ontario Institute for Cancer Research (OICR), Ottawa Hospital Research Institute (OHRI), and the University of Toronto. To accelerate the development of its own investment portfolio in Canada, Versant has also established a network of laboratories across the country called Discovery Engines. These include Inception Sciences in Vancouver and Montreal, and Blueline Bioscience in Toronto. To date several new projects have been launched in the fields of oncology, ophthalmology and inflammatory diseases, some having secured series A backing from Versant and pharmaceutical partners like Bayer and Celgene. “A common theme is to catalyze the creation of companies and accelerate their maturation with our own resources and those of global pharmaceutical partners,” said Jerel Davis, Ph.D., managing director at Versant. “Our pan-Canadian portfolio spans multiple indications, with new companies built on world-class science and strategic partnerships. These startups need the capital resources to be successful, which historically had been a shortcoming of Canadian biotechs.” Canada has become a productive source of biotech investments for Versant. Versant’s Canadian footprint has grown to include three Discovery Engines that house more than 30 scientists, five fully backed companies, two seed investments and 10 academic grants supported by the firm. Together these investments represent more than CAD$500 million in committed capital from Versant, syndicate members and pharmaceutical partners. Versant Ventures is a leading healthcare investment firm committed to helping exceptional entrepreneurs build the next generation of great healthcare companies. The firm invests across the healthcare sector and at all stages of company development, with an emphasis on the discovery and development of novel therapeutics. With $1.9 billion under management and offices in North America and Europe, Versant has built a team with deep investment, operating, and scientific expertise that enables a hands-on approach to company building. Since the firm's founding in 1999, more than 65 Versant companies have achieved successful acquisitions or IPOs. For more information, please visit

— Age Related Macular Degeneration - Companies Involved in Therapeutics Development are 3SBio Inc, AC Immune SA, Achillion Pharmaceuticals Inc, Aciont Inc, Acucela Inc, AdAlta Ltd, Adverum Biotechnologies Inc, Aerie Pharmaceuticals Inc, Aerpio Therapeutics Inc, Alimera Sciences Inc, Alkeus Pharmaceuticals Inc, Allergan Plc, Allinky Biopharma, Alteogen Inc, Amakem NV, Amarna Therapeutics BV, Ampio Pharmaceuticals Inc, Amyndas Pharmaceuticals LLC, ANP Technologies Inc, Apellis Pharmaceuticals Inc, Apexigen Inc, Applied Genetic Technologies Corp, Astellas Pharma Inc, Benitec Biopharma Ltd, Biokine Therapeutics Ltd, BioMAS Ltd, Biomics Biotechnologies Co Ltd, Biophytis SAS, BLR Bio LLC, Boehringer Ingelheim GmbH, Caladrius Biosciences Inc, Catalyst Biosciences Inc, Cell Cure Neurosciences Ltd, Cell Medica Ltd, Charlesson LLC, Chong Kun Dang Pharmaceutical Corp, Cipla Ltd, Clanotech AB, Clearside BioMedical Inc, Coherus BioSciences Inc, Colby Pharmaceutical Company, Crinetics Pharmaceuticals Inc, Critical Pharmaceuticals Ltd, Daiichi Sankyo Company Ltd, Diffusion Pharmaceuticals Inc, Dong-A Socio Holdings Co Ltd, Eleven Biotherapeutics Inc., Elsalys Biotech SAS, Exonate Ltd, F. Hoffmann-La Roche Ltd, FirstString Research Inc, Foamix Pharmaceuticals Ltd, Formycon AG, Gene Techno Science Co Ltd, Genentech Inc, GenSight Biologics SA, GlaxoSmithKline Plc, Graybug Vision Inc, Grupo Ferrer Internacional SA, HanAll Biopharma Co Ltd, Huabo Biopharm Co Ltd, iCo Therapeutics Inc., Icon Bioscience Inc, Iconic Therapeutics Inc, Inception Sciences Inc, Innovent Biologics Inc, Intellect Neurosciences Inc, International Stem Cell Corp, Ionis Pharmaceuticals Inc, Jeil Pharmaceutical Co Ltd, Johnson & Johnson, Kala Pharmaceuticals Inc, Kodiak Sciences Inc, Lead Discovery Center GmbH, LeadArtis SL, M's Science Corp, Mabion SA, MacuCLEAR Inc, MeiraGTx Ltd, Mitotech SA, Mitsubishi Tanabe Pharma Corp, Mor Research Application Ltd, Navigen Pharmaceuticals Inc, Navya Biologicals Pvt Ltd, Neovacs SA, Neumedicines Inc, Neuroptis Biotech, Novartis AG, NovelMed Therapeutics Inc, Ocular Therapeutix Inc, Ohr Pharmaceutical Inc, Omeros Corp, Ophthotech Corp, Oxford BioMedica Plc, PanOptica Inc, Pfenex Inc, Pfizer Inc, Precision Ocular Ltd, Promedior Inc, pSivida Corp, QLT Inc, Ra Pharmaceuticals Inc, Regeneron Pharmaceuticals Inc, RegenxBio Inc, Retrotope Inc, Ribomic Inc, RXi Pharmaceuticals Corp, Samumed LLC, SanBio Inc, Santen Pharmaceutical Co Ltd, SciFluor Life Sciences LLC, Stealth BioTherapeutics Inc, Sucampo Pharmaceuticals Inc, Sumitomo Dainippon Pharma Co Ltd, Sun Pharma Advanced Research Company Ltd, TRACON Pharmaceuticals Inc, TWi Pharmaceuticals Inc, Tyrogenex Inc, Wellstat Ophthalmics Corp and Xbrane Biopharma AB. Age related macular degeneration is the most common reason for vision loss in people aged above 50. It results in depreciation of the macula that may lead to distorted or blurry central vision. The predisposing factors involved are age, smoking, sunlight, heredity etc. Symptoms include development of blind spot and hazy vision. The condition may be treated by photodynamic therapy, radiation therapy and medication such as anti-angiogenic drugs. The Age Related Macular Degeneration (Ophthalmology) pipeline guide also reviews of key players involved in therapeutic development for Age Related Macular Degeneration and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Pre-Registration, Phase III, Phase II, Phase I, Preclinical and Discovery stages are 1, 8, 33, 11, 109 and 31 respectively. Similarly, the Universities portfolio in Phase II, Preclinical and Discovery stages comprises 1, 15 and 2 molecules, respectively. Age Related Macular Degeneration (Ophthalmology) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Direct’s proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Inquire more about this research at Note:Certain content / sections in the pipeline guide may be removed or altered based on the availability and relevance of data. • The pipeline guide provides a snapshot of the global therapeutic landscape of Age Related Macular Degeneration (Ophthalmology). • The pipeline guide reviews pipeline therapeutics for Age Related Macular Degeneration (Ophthalmology) by companies and universities/research institutes based on information derived from company and industry-specific sources. • The pipeline guide covers pipeline products based on several stages of development ranging from pre-registration till discovery and undisclosed stages. • The pipeline guide features descriptive drug profiles for the pipeline products which comprise, product description, descriptive licensing and collaboration details, R&D brief, MoA & other developmental activities. • The pipeline guide reviews key companies involved in Age Related Macular Degeneration (Ophthalmology) therapeutics and enlists all their major and minor projects. • The pipeline guide evaluates Age Related Macular Degeneration (Ophthalmology) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. • The pipeline guide encapsulates all the dormant and discontinued pipeline projects. • The pipeline guide reviews latest news related to pipeline therapeutics for Age Related Macular Degeneration (Ophthalmology) • Procure strategically important competitor information, analysis, and insights to formulate effective R&D strategies. • Recognize emerging players with potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. • Find and recognize significant and varied types of therapeutics under development for Age Related Macular Degeneration (Ophthalmology). • Classify potential new clients or partners in the target demographic. • Develop tactical initiatives by understanding the focus areas of leading companies. • Plan mergers and acquisitions meritoriously by identifying key players and it’s most promising pipeline therapeutics. • Formulate corrective measures for pipeline projects by understanding Age Related Macular Degeneration (Ophthalmology) pipeline depth and focus of Indication therapeutics. • Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope. • Adjust the therapeutic portfolio by recognizing discontinued projects and understand from the know-how what drove them from pipeline. For more information, please visit

Zhuo Y.,Merck And Co. | Gauthier J.-Y.,Pharmascience | Black W.C.,Kaneq Pharma Inc. | Percival M.D.,Inception Sciences | Duong L.T.,Merck And Co.
Bone | Year: 2014

The cathepsin K (CatK) inhibitor odanacatib (ODN) is currently being developed for the treatment of osteoporosis. In clinical trials, efficacy and resolution of effect of ODN treatment on bone turnover biomarkers and accrued bone mass have been demonstrated. Here, we examine the effects of continuing treatment and discontinuation of ODN versus alendronate (ALN) on osteoclast (OC) function. First, accessibility and reversible engagement of active CatK in intracellular vesicles and resorption lacunae of actively resorbing OCs were demonstrated by the selective and reversible CatK inhibitors, BODIPY-L-226 (IC50=39nM) and L-873,724 (IC50=0.5nM). Next, mature human OCs on bone slices were treated with vehicle, ODN, or ALN for 2days, followed by either continuing with the same treatment, or replacement of the inhibitors by vehicle for additional times as specified per experimental conditions. Maintaining OCs on ODN or ALN significantly reduced CTx-I release compared to vehicle controls. However, only the treatment of OCs with ODN resulted in the formation of small shallow discrete resorption pits, retention of intracellular vesicles enriched with CatK and other lysosomal enzymes, increase in 1-CTP release and number of TRAP(+) OCs. Upon discontinuation of ODN treatment, OCs rapidly resumed bone resorption activity, as demonstrated by a return of OC functional markers (CTx-I, 1-CTP), cell number and size, morphology and number of resorption pits, and vesicular secretion of CatK toward the respective vehicle levels. As expected, discontinuation of ALN did not reverse the treatment-related inhibition of OC activity in the time frame of the experiment. In summary, this study demonstrated rapid kinetics of inhibition and reversibility of the effects of ODN on OC bone resorption, that differentiated the cellular mechanism of CatK inhibition from that of the bisphosphate antiresorptive ALN. © 2014 Elsevier Inc..

Fortelny N.,University of British Columbia | Cox J.H.,University of British Columbia | Cox J.H.,Inception Sciences | Kappelhoff R.,University of British Columbia | And 5 more authors.
PLoS Biology | Year: 2014

Proteolytic processing is an irreversible posttranslational modification affecting a large portion of the proteome. Protease-cleaved mediators frequently exhibit altered activity, and biological pathways are often regulated by proteolytic processing. Many of these mechanisms have not been appreciated as being protease-dependent, and the potential in unraveling a complex new dimension of biological control is increasingly recognized. Proteases are currently believed to act individually or in isolated cascades. However, conclusive but scattered biochemical evidence indicates broader regulation of proteases by protease and inhibitor interactions. Therefore, to systematically study such interactions, we assembled curated protease cleavage and inhibition data into a global, computational representation, termed the protease web. This revealed that proteases pervasively influence the activity of other proteases directly or by cleaving intermediate proteases or protease inhibitors. The protease web spans four classes of proteases and inhibitors and so links both recently and classically described protease groups and cascades, which can no longer be viewed as operating in isolation in vivo. We demonstrated that this observation, termed reachability, is robust to alterations in the data and will only increase in the future as additional data are added. We further show how subnetworks of the web are operational in 23 different tissues reflecting different phenotypes. We applied our network to develop novel insights into biologically relevant protease interactions using cell-specific proteases of the polymorphonuclear leukocyte as a system. Predictions from the protease web on the activity of matrix metalloproteinase 8 (MMP8) and neutrophil elastase being linked by an inactivating cleavage of serpinA1 by MMP8 were validated and explain perplexing Mmp8-/- versus wild-type polymorphonuclear chemokine cleavages in vivo. Our findings supply systematically derived and validated evidence for the existence of the protease web, a network that affects the activity of most proteases and thereby influences the functional state of the proteome and cell activity. © 2014 Fortelny et al.

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