Nigel Greig - US grants
Affiliations: | Drug Design and Development | National Institute of Aging, Cabanatuan City, Central Luzon, Philippines |
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High-probability grants
According to our matching algorithm, Nigel Greig is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2018 | Greig, Nigel H. | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Design and Development of Experimental Therapeutics @ Aging 1. Alzheimers Disease: Three series of agents are being developed to treat AD. Selective inhibitors of amyloid-beta peptide (abeta) production and inhibitors of the enzymes acetylcholinesterase (AChE) and butrylcholinesterase (BChE) 1.1. Molecular events associated with AD: A reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as an important therapeutic goal in AD. Targets to achieve this goal are factors that affect the expression and processing of the Abeta precursor protein (APP). Our studies have generated compounds to lower APP and Abeta levels in neuronal cultures and the brain of animal models without toxicity. This activity is independent of cholinergic action, but is post-transcriptional: lowering APP protein levels without affecting mRNA levels via translational regulation. This is mediated, in part, via the 5-untranslated region (UTR) of APP mRNA. Current studies are characterizing mechanisms involved and focusing on these in the design and synthesis of agents that lower APP levels as a way of lower Abeta peptide (collaborators: Drs. Lahiri, Sambamurti, Rogers). The compound, Posiphen, has advanced to clinical trials and backup compounds are being assessed to define molecular mechanisms underpinning activity. Posiphen was well tolerated in phase 1 clinical trials, demonstrating target engagement and effectively lowering APP, Abeta, tau and other key AD CSF markers (collaborator: Dr. Maccecchini). Recent parallel studies (collaborator: Drs. Rogers, Lahiri, Sambamurti, Maccecchini) indicate that Posiphen has a broader action that impacts a number of misfolded proteins, including alpha-synuclein. Hence Posiphen and metabolites are being assessed in cellular and animal models of Parkinson's disease (PD) as well as other neurological disorders. 1.2. Cholinesterase inhibitors: Compounds were developed to optimally augment the cholinergic system in the elderly and raise levels of the neurotransmitter, acetylcholine (ACh). Extensive studies involving chemistry, X-ray crystallography, biochemistry and pharmacology resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in the brain or periphery for an optimal duration for the potential treatment of a variety of disorders (AD, myasthenia gravis, and as chemical warfare prophylactics (collaborators: Drs. Becker, Marini, Lahiri, Kamal, Reale, Sambamurti, Descamp). Also, specific and highly selective BChE inhibitors have been developed to define this enzyme's role in brain during health, aging and disease. 1.2A. AChE: Long-acting, centrally active, selective inhibitors of AChE have been developed to define its role in health and disease and move compounds into clinical studies. Extensive chemistry on the template of eserine has been undertaken. Novel phenylcarbamates were developed that are highly selective for AChE vs. BChE, have favorable toxicologic profiles, robustly enhance cognition in animal models and are neurotrophic/protective. In collaborative studies phenserine was translated into clinical trials in AD (collaborators: Drs. Becker, Nordberg, Friedhoff, Winblad, Sambamurti, Lahiri, Bruinsma). Generation of a slow-release formulation has been undertaken - for future human studies (Collaborators, Drs. Becker, Chigurupati, Flanagan). Recent studies have notably demonstrated that (-)-Phenserine is highly effective in protecting against brain injury (stroke and TBI) providing potent anti-apoptotic actions across cellular and in vivo models, and new analogues have been synthesized and are under evaluation. 1.1B. BChE: In healthy brain, 80% of cholinesterase activity is in the form of AChE and 20% is BChE. AChE activity is concentrated chiefly in neurons, and BChE primarily with glial cells. Kinetic evidence indicates a role for BChE, in hydrolysing excess ACh. In advanced AD, AChE activity declines to 15% of normal levels in affected brain regions, whereas BChE activity rises 2-fold. The normal BChE/AChE ratio becomes mismatched in AD causing excess metabolism of already depleted ACh. The first reversible, centrally-active BChE inhibitors have been synthesized and appear favorable in AD preclinical models. Bisnorcymserine has been advanced through required preclinical studies and into clinical phase 1 studies where its safety, pharmacokinetics and -dynamics are being assessed (collaborators: Drs. Kapogiannis, Maccecchini, Lahiri, Kamal) 1.3. Utilizing the compounds generated above, the relationship between the cholinergic system and inflammation is being characterized in health and disease (collaborators: Drs. Reale, Kamal). Our recent studies suggest that the cholinergic anti-inflammatory pathway is compromised in AD, but can potentially be effectively reset by select (-)-phenserine analogs 2. Stroke, PD, brain trauma: Drugs currently used provide temporary relief of symptoms, but do not prevent the occurrence of cell death. Our target for drug design is the transcription factor, p53 and its down-stream effectors. p53 up-regulation is a common feature of many neurodegenerative disorders and a gatekeeper to the biochemical cascade that leads to apoptosis. We developed novel tetrahydrobenzothiazole/oxazole analogs that inhibit p53 activity. Agents are in current assessment for neuroprotective/regenerative actions in cellular and animal models (collaborators: Drs. Pick, Hoffer, Wang, Luo) to define whether neurons can be rescued for apoptotic cell death. Our p53 inactivators have demonstrated potent activity in models of stroke, AD, PD, and are in assessment in other disorders - including traumatic brain injury (TBI) - to define their optimal use. In parallel with evaluating whether neurons can be rescued from damage and dysfunction by inactivating p53 dependent apoptotic mechanisms that lead to cell death, we have been evaluating the experimental drug (-)-phenserine tartrate in animal models of TBI and stroke, and have demonstrated both antiapoptotic and anti-inflammatory actions that result in reduced neuronal cell death and the mitigation of behavioral impairments, and are evaluating translational potential of this approach for clinical studies 3. Clinical translation and assessment of experimental drugs in neuropsychiatric conditions: Despite promising advances in understanding possible mechanisms of disease in recent years, clinical investigators still struggle with methods and practices too open to effects from measurement errors, biases, carelessness at research sites distant from the sponsor, and with commercial pressures to as quickly as possible enter human trials - a priority that is acknowledged to allow frequently insufficient preclinical investigations and suspected as one cause for failures in human clinical trials. Hence, drug discovery/development is acknowledged as at great risks of failing due to lack of efficacy or compromises to safety. Less than 11% of all new agents that enter clinical development reach the marketplace. For neurological drugs, attrition is considerably higher still, less than 7%. To understand and optimize clinical development the numerous factors that impair the process and generate type 2 errors are being critically reviewed and assessed (Collaborator: Dr. Becker). Rational approaches to optimize the clinical drug development process of neuropsychiatric drugs are being developed to aid reduce the currently too high attrition rate in neurological drug development, and particularly in AD. |
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2018 | Greig, Nigel H. | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Neuroprotective Role of Glp-1 Receptor Agonists @ Aging Type 2 diabetes mellitus (T2DM) is a prevalent disease in the elderly for which current treatments are available, but not satisfactory. It is a chronic, age-related degenerative disorder that is a leading cause of morbidity and mortality in the elderly, and has attained epidemic proportion, with in excess of 171 afflicted worldwide (Wild et al., Diabetes Care 27:104753, 2004). A variety of risk factors have been implicated in the development of T2DM (Gtz et al., Cell Mol Life Sci 66:1321-5, 2009; Jin & Patti, Clin Sci (Lond) 116:99-111, 2009), including a genetic predisposition, age, oxidative stress, obesity, diet, and physical inactivity. By comparison, several of these same factors appear to be involved in neurodegenerative disorders, such as Alzheimer's disease (AD), the most common form of dementia (Reddy et al., J Alzheimers Dis 16:763-74, 2009; Luchsinger & Gustafson, J Alzheimers Dis 16:693-704, 2009). Interestingly, a number of well-designed epidemiological studies have established a link between these two diseases, together with others, including Parkinson's disease (PD) and stroke, identifying T2DM as a risk factor for developing various chronic and acute neurodegenerative disorders (Toro et al., J Alzheimers Dis 16:687-91, 2009; Craft, Curr Alzheimer Res 4:147-52, 2007). The pancreas and brain are both highly insulin sensitive tissues. T2DM and AD, together with other neurological conditions, share several clinical and biochemical features. Particularly important amongst these is an impaired insulin signaling, suggesting overlapping pathogenic mechanisms. Hence, an effective treatment strategy in one disease could have potential value in the other. A recent effective treatment strategy in T2DM is the use of incretin-based therapies based on the insulinotropic actions of the endogenous peptide, glucagon-like peptide-1 (GLP-1), utilizing the long-acting analog exendin-4 (Ex-4) (Lovshin & Drucker, Nat Rev Endocrinol 5:262-9, 2009; Drucker, Diabetes 62:3316-23, 2013). The acute actions of GLP-1 and receptor (R) agonists on beta-cells include stimulation of glucose-dependent insulin release, augmentation of insulin biosynthesis and stimulation of insulin gene transcription. Chronic actions include stimulation of beta-cell proliferation, induction of islet neogenesis and inhibition of beta-cell apoptosis that, together, promote expansion of beta-cell mass and the normalization of insulin signaling (Drucker, Diabetes 64:317-26, 2015). Ex-4 has been reported to readily enter the brain (Kastin et al., Int J Obes Relat Metab Disord 27:313-8, 2003), where the GLP-1R is expressed widely (Perry & Greig, Trends Pharmacol Sci 24:377-83, 2003) and its activation results in multiple biological responses. GLP-1R stimulation in brain is classically allied to regulation of appetite and satiety (Lovshin & Drucker ibid, 2008). More recently, however, it has been associated with neurotrophic (Perry et al., J Pharmacol Exp Ther 300:958-66, 2002) and neuroprotective actions in both cellular and in vivo models of acute and chronic neurodegenerative conditions (Perry et al., J Pharmacol Exp There 302:881-8., 2002; Perry et al., J Neurosci Res 72:603-12, 2003), including stroke, AD, PD and Huntingtons disease (HD) (Li et al., PNAS 106:1285-90, 2009; Li et al., J Alz Dis 19:1205-19, 2010; Harkavyi et al., J Neuroinflamm 21:519, 2008; Martin et al., Diabetes 58:318-28, 2009; Bertilsson et al., J Neurosci Res 86:326-38, 2008). Our target for drug design is the glucagon-like peptide-1 (GLP-1) receptor (R). GLP-1 is secreted from the gut in response to food and is a potent secretagogue that binds to the GLP-1R on pancreatic beta-cells to induce glucose-dependent insulin secretion, thereby controling plasma glucose levels. We are developing and evaluating long-acting GLP-1 analogues (collaborators: Drs. Egan, Hoffer, Lahiri, Sambamurti, Mattson). This research aided in the development of the peptide exendin-4 (Ex-4) into clinicall studies in type 2 diabetes. Novel chimeric peptides that combine the best features of GLP-1 and Ex-4 have also been designed and assessed in a variety preclinical models (Wang et al., J Clin Invest 99:2883-9, 1997, DeOre et al., J Gerontol A Biol Sci Med Sci 52:B245-9, 1997; Greig et al., Diabetologia 42:45-50, 1999; Szayna et al., Endocrinol 141:1936-41, 2000; Doyle et al., Endocrinol 142:4462-8, 2001; Doyle et al., Regul Pept 114:153-8, 2003; Doyle et al., Endocrine 27:1-9, 2005). We are characterizing the role of GLP-1R stimulation in the nervous system, as it is found present in brain and peripheral nerve. Our collaborative studies were the first to define that GLP-1 analogues possess neurotrophic properties and protect neuronal cells from a wide variety of lethal insults. Neuroprotection in cell culture translated to in vivo studies in classical rodent neurodegeneration models, which include AD, stroke, PD, HD, ALS, traumatic brain injury and peripheral neuropathy (Perry et al., Exp Neurol 203:293-301, 2007; Li et al., PNAS 106:1285-90, 2009; Li et al., J Alz Dis. 19:1205-19, 2010, Li et al., PLoS One 7:e32008, 2012; Salcedo et al., Br J Pharmacol 166:1586-99, 2012; Tweedie et al., Exp Neurol 239:170-82, 2013; Rachmany et al., Age 35:1621-36, 2013; Tweedie et al., Neurobiol Dis 54:1-11, 2013; Eakin et al., PLoS One 8:e82016, 2013; Greig et al., Alzheimers Dement. 10(S1):S62-7, 2014; Tweedie et al., Alzheimers Dement. 12:34-48, 2016). Current studies are focused on selecting agents for clinical assessment and defining mechanisms underpinning the neurotrophic/neuroprotective actions (Li et al., J Neurochem 113:621-31, 2010; Li et al., J Neurochem 135:1203-17, 2015). Additional research is focused on optimizing the translation of Ex-4 for the treatment of neurodegenerative disorders, and defining which specific disorders are most likely to have a clinical response. Specifically, the long-acting GLP-1 receptor agonist exendin-4 has been evaluated in human MCI/early AD (Collaborators: Drs. Kapogiannis, Egan, Mattson) and a trial in PD has been completed (Lancet 2017; Collaborators: Drs. Foltynie, Athauda). Other clinical trials in different disorders are in current planning involving a sustained-release formulation of Ex-4 (PT302, Peptron, S. Korea) (Collaborators: Drs. Kim and Peptron colleagues; Hoffer; Chiang, Wang, Pick). An alternate approach is to augment the levels of endogenous incretins available within the body by inhibiting their metabolism and, thereby, elevate their levels. In this regard, GLP-1 and the incretin, glucose-dependent insulinotropic polypeptide (GIP) are released following food ingestion and bind to their respective receptors on pancreatic beta cells to induce insulin secretion. Receptors for these endogenous peptides are found throughout the body, including the brain - which both GLP-1 and GIP can readily enter. The presence of the metabolizing serine protease enzyme, dipeptidyl peptidase-4 (DPP-4), results in the rapid clearance of both incretins. Current studies are assessing the utility of selective and well tolerated DPP-4 inhibitors in cellular and preclinical animal studies to elevate available GLP-1 and GIP levels in plasma and brain to a level at which they may provide neurotrophic/protective actions for the treatment of neurodegenerative disorders. Still other approaches being evaluated involve augmenting GIP-R and GLP-1R stimulation separately and together by the use of dual incretin mimetic peptides, and tri-incretin mimetics to the glucagon receptor too. Ongoing studies are in preclinical stages to both evaluate new drug development and drug repurposing towards neurological disorders currently lacking effective pharmacological treatment where this incretin strategy could prove highly beneficial (Collaborators: Drs. Wang, Hoffer, Tones, Zaleska, Mattison, Kim, DiMarchi) |
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2018 | Greig, Nigel H. | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Pro-Inflammatory Cytokine Lowering Anti-Inflammatory Drugs @ Aging Tumor necrosis factor- (TNF) is one of the primary pro-inflammatory cytokines synthesized and released by microglial cells. Once TNF is released, it may initiate a self-propagating cycle of unchecked inflammation (Frankola et al., CNS Neurol Disord Drug Targets 10:391-403, 2011). Pharmacological intervention to interrupt this cycle may be of significant benefit in the setting of neuroinflammation-mediated diseases. In 1993, Moreira et al., (J Exp Med 177:1675-80, 1993) described a series of studies showing that the drug thalidomide (THAL) was able to lower TNF protein levels post-transcriptionally by accelerating degradation of its mRNA. Unfortunately THAL is not a particularly potent TNF lowering agent induces serious teratogenic adverse effects to embryos in utero, sedation and peripheral neuropathy at clinical doses. Nevertheless, the observation of THALs TNF lowering activity gave rise to studies to differentiate these actions, understand THALs TNF structure/activity relationship and develop more potent analogs. In principle, the identification of analogs with enhanced anti-TNF activity and reduced teratogenic and neurotoxic effects may provide a viable treatment strategy for CNS neuroinflammatory and other forms of inflammatory disease. Our medicinal chemistry modifications to the backbone of THAL and newer analogs (namely pomalidomide (POM)) are generating an extensive library of novel agents (successfully issued US patents owned by NIA: 7,973,057 and 8,927,725, and U.S. Patent Application No. 62/235,105 filed September 30, 2015). Our focus is identify well-tolerated drug-like compounds with more potent anti-TNF activity from our generated library and develop these as experimental drugs to characterize the role of the neuroinflammatory component in and to treat Alzheimer's disease (AD) and associated disorders. Problem and Focused Aims: AD is a complex disorder that manifests as progressive dementia with few other symptoms. With a long meandering course, AD is associated with deposits of amyloid-B protein (AB) as much as 20 years prior to the development of dementia. It also induces intracellular accumulation of the microtubule-associated protein Tau (MAPT) as neurofibrillary tangles (NFTs) that correlate more closely with the extent of dementia (Baranello et al., Curr Alzheimer Res 12:32-46, 2015). NFTs arise some 10 years after AB and brain atrophy follows after five further years. However, the resilience and redundancy of the brain protects the affected subject from dementia for around five further years after the detection of atrophy by brain image analysis. Experimental drugs and strategies that reduce the generation of AB oligomers and aggregates as well as of phosphorylated-tau have formed, in large part, the basis of treatment strategies thus far developed to combat the development of AD. Whereas these target are considered the initiators of the cascade of events that become self-propagating and then drive AD progression, their toxicity may not be the direct cause of neurodegeneration. This premise may account for the failure of anti-amyloid and anti-tau therapies in clinical AD trials when administered late in the disease course (Becker et al., Nature Rev Drug Discov 13:156, 2014). The presence of soluble and insoluble AB and MAPT can induce microglia activation (McGeer & McGeer, Acta Neuropathol 126:479-97, 2013), and direct evidence of neuroinflammation in AD brain has been shown by in vivo PET imaging (Schuitemaker et al., Neurobiol Aging 34:12836, 2013). Notably, levels of pro-inflammatory cytokines are elevated in plasma and CSF from AD patients, for TNF by as much as 25-fold (Tarkowski et al., J Clin Immunol 19:223-30, 1999). In MCI subjects that progress to develop AD, a rise in CSF TNF levels correlates with disease progression (Tarkowski et al., J Neurol Neurosurg Psychiatry 74:1200-5, 2003). Paralleling this, elevated expression of TNF is reported within the entorhinal cortex of 3xTg-AD mice prior to the appearance of amyloid and tau pathology, and this increase associates with the onset of cognitive deficits in these mice and later neuronal loss (Janelsins et al. J Neuroinflamm 2:23, 2005). We hypothesize that failure of protein homeostasis leads to accumulation of proteins (e.g., A, APOE and MAPT) that induce microglial activation and a proinflammatory M1 response to instigate their removal. The continuing generation of protein (AB, APOE and MAPT) leads to maintenance of a chronic M1 response, an impairment of transition to an anti-inflammatory M2 response (particularly in the aging brain that is already vulnerable to inflammation) with ensuing neuronal impairment observed in the animal models and in preclinical AD that eventually leads to cell death. Proinflammatory cytokines, like TNF, induce vascular changes to allow lymphocyte infiltration that may underpin reported cerebral vasculature leakiness of AD patients and related Tg mouse models. Moreover, TNF induces AB production in cellular and animal AD models, further increasing its accumulation and accelerating the entire cascade. Our focus is to understand the time course of development of neuropathology accumulation of inflammatory cytokines and behavioral deficits in mouse models that may reflect the disease pathology in humans. Our aim is to use these models, together with classical evaluations of pharmcokinetics/dynamics and toxicity evaluations, to aid select out from our agents that potently lower TNF - compounds that can be moved to the clinic to mitigate the neuroinflammatory element in AD and associated disorders. Our studies involve: (i) Synthetic chemistry on the backbones of THAL and POM to generate more potent anti-inflammatory agents that are better tolerated. (ii) Cellular screening for anti-inflammatory actions (Tweedie et al., J Neuroinflamm 9:106, 2012) (iii) Zebrafish and chicken embryo screening for anti-inflammatory, anti-angiogenesis and toxicology screening (Collaborators: Drs. Vargesson, Figg, Beedie) (Mahony et al., PNAS 110:12703-8, 2013; Beedie et al., Oncotarget (Epub ahead of print) 2016). (iv) Pharmacokinetic/dynamic/toxicological evaluations in acute rodent studies. (v) Efficacy evaluations in both acute and chronic rodent models involving inflammation, cognitive impairment and/or AD and related disorders (Russo et al., J Neurochem. 122:11871-92, 2012; Tweedie et al., J Neuroinflamm 9:106, 2012; Belarbi et al., J Neuroinflamm 9:23, 2012; Starke et al., J Neuroinflammation 11:77, 2014; Baratz et al., J Neuroinflamm 12:45, 2015.; Wang et al., J Neuroinflamm 13:168, 2016). In synopsis: Our focus is to use our novel compounds as agents to understand the time-dependent role of neuroinflammation in AD progression in animal models and, concurrently, to select out the most potent with drug-like features as a new treatment intervention for AD and related disorders, creating a preclinical package both on our best agent as well as on the comparator clinically approved cancer drug, POM (as a back up), to support clinical translation. Notably, the drug target in these proposed studies - elevated levels of TNF - has relevance to AD (with the potential to impact acute and chronic neurological endpoints) and to related CNS and systemic disorders driven by inflammation (for independent review see: Tobinick E; Curr Alzheimer Res. 9:99-109, 2012; Ignatowski T et al., CNS Drugs. 28(8):679-97, 2014; Clark & Vissel, J Neuroinflamm ;13:236, 2016). We additionally evaluate our TNF lowering agents in other neurological disorders in which an inflammatory state is evident, and for which effective treatments are lacking (such as TBI, stroke and Bilirubin-induced Neurological Dysfunction). |
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