16 April 2004. Last month, the commercial conference planner IBC Screentech held a conference on drug development approaches in neurodegeneration in San Diego, California, as part of its World Summit series. Dora Kovacs, of Massachusetts General Hospital in Charlestown, contributed meeting notes on topics of interest selected by Alzforum editors. Many excellent presentations could not be covered in detail, but to give our readers a flavor of the topics featured at this conference, we have appended Kovacs’s summaries with brief speaker abstracts.
Lee Rubin, Curis, Inc., presented data suggesting that small-molecule hedgehog agonists might prove useful as neuroprotectants. He began by asking whether it was possible to produce drugs that would stimulate repair of damaged tissues. Innate stem cells proliferate provided they receive enough mitogens, which are their limiting factors. The sonic hedgehog signaling pathway functions to regulate proliferation of adult stem cells (see ARF related news story), and overexpression of hedgehog induces neural cell proliferation in adult mice. Mobilizing controlled proliferation of natural stem cells in the hippocampus, for example, might be better than transplantation to effect neural repair. Rubin cited a paper by Santarelli et al., 2003, which suggests that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
Rubin reported that Curis has discovered a family of small-molecule hedgehog agonists that, when administered to pregnant mice, reach the embryo and elevate hedgehog signaling. They also act on the adult CNS when given orally. They have a stronger effect on stem cell proliferation in the adult hippocampus than does Prozac and are being tested for their effects in rodent models of depression. Interestingly, such agonists also reduce neuronal damage in ischemic brains.
To date, no negative effects have been observed with the use of these compounds, though others have cautioned that cell proliferation must be carefully monitored in developing such drugs. Wyeth Pharma is in the process of evaluating these compounds for use in AD patients. Rubin concluded that small-molecule hedgehog agonists have therapeutic potential for other neurodegenerative diseases, as well.
Lit-Fui Lau, Pfizer, Inc., and Karen Duff, Nathan Kline Institute, summarized recent developments in preventing tau pathology. Lau reviewed the role of protein kinases in neurodegeneration. Construction of animal models that could recapitulate tau pathology is key to understanding the factors that regulate pretangle and tangle formation, as well as ultimate neurodegeneration. P25/Cdk5 transgenic mice were reported to develop pretangles, but not full-fledged tangles (Ahlijanian et al., 2000). Recently, inducible transgenic mouse lines were made in which overexpression of p25 in the postnatal forebrain directed Cdk5 to its pathological substrates. In these animals, endogenous tau aggregated, and neurofibrillary pathology developed with neuronal loss in the cortex and hippocampus, amongst other pathological changes (Cruz et al., 2003). Lau proposed that, when tau kinases are moderately stimulated, additional unknown factors are required for the conversion of pretangles to tangles. Aβ, which perhaps activates Cdk5, GSK3β, and MAPK only moderately, cannot induce pretangle or tangle formation in mouse models; it can only enhance the formation of tangles once they already exist. Lau suggested a modification of the amyloid cascade hypothesis in which Aβ alone is insufficient to induce tau pathologies; unknown environmental factors (e.g., aging-related physiological changes, head trauma, silent ischemic attacks, etc.) may also be required.
Duff and her collaborators recently published their findings (Noble et al., 2003) that enhanced kinase activity (Cdk5) leads to accelerated and enhanced tau pathology in vivo. They crossed a mouse overexpressing the Cdk5 activator p25 with a mutant tau mouse (JNPL3 line) and showed elevated levels of insoluble, hyperphosphorylated tau and NFTs in the double transgenics. Data was presented showing that a kinase inhibitor (LiCl, inhibits GSK3) can reduce the level of insoluble tau, but only if administered to tau transgenic mice late during their pathology progression. Administration earlier led to increased insoluble tau, probably through some interaction between p25/Cdk5 and GSK. Duff concluded that kinase inhibitors may be beneficial therapeutically. Duff also presented a recently published mouse line. The hTau line expresses all six isoforms of wild-type human tau in the absence of endogenous mouse tau, and makes neurofibrillary tangles in the cortex and hippocampus (Andorfer et al., 2003).
Sam Gandy, Thomas Jefferson University, and Mark Burns, Nathan Kline Institute, discussed the potential of antiamyloid treatments, such as statins and metal-binding agents, in the treatment of AD. Gandy examined the effect of six months of vaccination on a small sample of 20-year-old rhesus monkeys (see ARF related news story). The animals were too young to develop plaque pathology, but vaccinated monkeys responded with increased Aβ levels in plasma. Upcoming clinical trials of importance include phase III trials with cerebril and clioquinol. Made by Neurochem Inc., cerebril just completed a phase II trial for the prevention of hemorrhagic stroke caused by cerebral amyloid angiopathy (see ARF Live Discussion on CAA), and is expected to enter phase III within the year. Clioquinol, an antibiotic with metal-binding properties, will enter Phase III trials in either the U.S. or the U.K., depending on where financial support can be secured (see ARF Live Discussion on clioquinol).
Statins look promising for regulating APP processing. Atorvastatin promotes α-secretase cleavage of APP while inhibiting Aβ generation. The mechanism of atorvastatin’s effect on secretase cleavage is not well-characterized. Gandy showed data indicating that factors regulating intracellular signaling pathways and endocytosis are involved in this process.
Burns examined a potential new mechanism of action of simvastatin. When administered to PS/APP mice, this statin inhibits γ-, but not α- or β-secretase activities as indicated by unchanged sAPP and increased βCTF levels. Thus, simvastatin and atorvastatin differ in their effect on βCTF levels, which are decreased by atorvastatin. In vitro, simvastatin appears to directly inhibit γ-secretase activity in lipid rafts. Lovastatin, but not atorvastatin or methyl-β-cyclodextrin, also reduces γ-secretase activity in these membrane fractions. These data add another level of complexity to the mechanisms of action attributed to statins in AD.—Dora Kovacs.
Joseph Rogers, Sun Health Research Institute. Pathogenic and Therapeutic Actions of Alzheimer’s Inflammation: Can We Control One and Keep the Other?
Many inflammatory mechanisms subserve beneficial but inherently destructive functions such as detecting, attacking, and removing pathogens. Clearance of Aβ in AD may be an example. In brain, however, inflammatory control and regenerative capacities may be limited, so that stimulating a beneficial mechanism may ultimately have significant deleterious consequences. Understanding the complex molecular pathways of inflammation may provide new therapeutic targets and a way out of this dilemma.
Lawrence M. Zaccaro, Pfizer. Maximizing Utility of Tools in Neurodegenerative Research: Benefiting Patient, Corporations and Universities.
Future discovery and general availability of tools used in early research for treatment of AD remain key ingredients for the further elucidation of the causes and a potential cure for neurodegenerative diseases. Availability to any research organization at reasonable costs, allowing broadest use and maximum utility, can benefit all parties, but most importantly, millions of patients in need (see ARF related news story).
Donald Kirsch, Cambria Biosciences. Genetic Model Organisms as Models for Neurodegenerative Disease
Yeast, worms, flies, and mice have been used as genetic model organisms in medical research. Mice provide excellent disease models including models for neurological disease. Yeast, worms, and flies offer flexible and efficient experimental systems. CNS targets can be functionally expressed in yeast, and worms and flies have true nervous systems. Pharmacological and disease models for neurodegeneration have been developed in these species and illustrative examples were presented.
Kelly R. Bales, Eli Lilly & Co. The APPV71F Transgenic Mouse Model of AD Reveals Impairing Effects of the Aβ Peptide(s)
Mouse models of AD confirmed the hypothesis that overexpression of genes associated with familial forms of AD results in region- and age-dependent deposition of the Aβ peptide(s) in brain parenchyma. Exactly how the Aβ peptide(s) disrupts normal neuronal function is unclear. Certain Aβ antibodies are able to prevent brain Aβ burden, as well as reverse previously characterized memory deficits in preclinical transgenic mouse models of AD (see ARF related news story).
William M. Pardridge, University of California, Los Angeles. Blood-Brain Barrier: The First Step in CNS Drug Development
Virtually 100 percent of large-molecule drugs and greater than 98 percent of small-molecule drugs do not cross the blood-brain barrier (BBB). Despite this situation, no pharmaceutical company in the world today has a BBB drug/gene targeting program. The BBB problem can be solved, and BBB solutions then enable the development of virtually any brain pharmaceutical.
Jeffry Vaught, Cephalon, Inc. New Therapeutics for Neurodegenerative Diseases
The primary pathology of neurodegenerative diseases is progressive loss of neurons, resulting in sequelae of clinical events. Targeting the molecular mechanisms that underlie neuronal death may revolutionize patient treatment. One signaling event, induced by a variety of insults and often preceding neuronal death, is activation of the c-Jun-N-terminal kinase (JNK) pathway. Molecular and pharmacological studies demonstrate that blockade of this pathway confers neuroprotection. Importantly, potential therapeutics are now under active clinical investigation.
Robert Hughes, Prolexys Pharmaceuticals, Inc. Using Proteomics to Discover Novel Targets in Huntington’s Disease
Huntington’s disease is a fatal neurodegenerative condition involving progressive motor and cognitive dysfunction. HD is caused by expansion of the glutamine-encoding CAG tract in the huntingtin protein. This causes huntingtin to acquire toxic properties associated with alterations in solubility and protein interactions. We are using a proteomics-based approach to map the network of huntingtin protein interactions in order to elucidate HD pathobiology and discover new drug targets for HD.
Sukanto Sinha, Elan Pharmaceuticals. Discovery of BACE, A Disease-Modifying Target for Alzheimer’s Disease (AD)
Understanding of AD has been increased over the last 15 years, yet its etiology remains unclear. Events leading to the formation of extracellular amyloid plaques play a key role in AD. Identification of the main biochemical players in amyloid peptide (Aβ) formation, especially BACE, and development of transgenic models exhibiting progressive disease pathology allow for validation of therapeutic approaches and for the reversal/slowing of disease pathology.
Martin Citron, Amgen, Inc. Secretase Inhibition and Other Anti-Amyloid Approaches for the Treatment of AD
Therapeutic approaches in the β-amyloid pathway range, from blocking production of Aβ42 with β- and γ-secretase inhibitors to efforts targeting existing plaques to immunotherapeutic strategies that may clear both monomers and mature deposits. Progress in BACE1 biology and improved understanding of γ-secretase continue to affect secretase inhibitor development.
Jeffrey S. Nye, Johnson & Johnson. NSAIDs: Mechanism of Modulating the γ-Secretase in AD
Drugs that modulate the γ-secretase to reduce Aβ(1-42) production but not the function of Notch, ErbB4, or other substrates would have advantages over classical γ-secretase inhibitors for Alzheimer’s disease therapeutics. We present data suggesting that the mechanism of action for NSAID-like modulators of the γ-secretase involves selective action at γ-site cleavages with relative sparing of ε-site cleavages for any substrate (see also ARF related news story).
Rudolph Tanzi, Massachusetts General Hospital. Alzheimer’s Disease: Genetic Clues for Novel Therapies
Alzheimer’s disease (AD) is an age-related neurodegenerative disease with complex inheritance. Genetic findings to date have prompted clinical trials aimed at curbing the production or enhancing the clearance of Aβ. The continuing identification of novel AD genes will ultimately allow for reliable prediction of AD risk and the development of novel strategies for treatment and prevention.
Dora Kovacs, Massachusetts General Hospital. Anti-Amyloid Approaches in AD-Based Intracellular Cholesterol Levels and Trafficking
Mounting evidence suggests a role for cholesterol metabolism in Aβ generation. Even fine imbalances in intracellular cholesterol distribution to lipid rafts, the Niemann-Pick C1 compartment, and cholesteryl-ester droplets can trigger major changes in Aβ production. ACAT inhibitors decrease cholesteryl-ester generation while also reducing amyloid plaque pathology in transgenic mouse models of AD.