Organizers: Howard Fillit (Alzheimer's Drug Discovery Foundation) and Jennifer Henry (The New York Academy of Sciences)Presented by the Brain Dysfunction Discussion Group and the Alzheimer's Drug Discovery Foundation
Reported by Pablo Ariel | Posted July 3, 2013
Alzheimer's disease (AD) is a terminal illness causing dementia and progressive neurological deterioration, and its prevalence increases dramatically as people age. In 2012 it was the sixth most frequent cause of death in the U.S., and the increasing death rate is expected to continue rising as the population ages. The CDC reports that the associated cost of health care was $200 billion in 2012 and is predicted to grow to $1.1 trillion by 2050. There is no cure: available drugs can alleviate some symptoms and slow progression, but none target the—still unclear—molecular mechanisms underlying the disease.
On May 6, 2013, the Academy's Brain Dysfunction Discussion Group, partnering with the Alzheimer's Drug Discovery Foundation, presented Translating Natural Products into Drugs for Alzheimer's and Neurodegenerative Disease. The symposium explored efforts to derive drugs from natural products, highlighting case studies of compounds at various stages of development for the treatment of AD and neurodegeneration.
Howard Fillit from the Alzheimer's Drug Discovery Foundation set the stage by reviewing the impact of Alzheimer's on public health, calling the disease an epidemic. He also described the opportunities for drug development from natural products. Despite a trend toward using synthetic chemical libraries for drug discovery, in the past decade more than a third of all approved drugs with a novel molecular mechanism of action have come from natural products.
David J. Newman from the National Cancer Institute, Grant J. Carr from AMRI, and Frank E. Koehn from Pfizer reviewed the advantages and challenges of developing drugs from natural products. Koehn began by defining natural products as "small molecules produced by organisms through secondary metabolism for biological purposes." This definition underscores a key advantage of using natural products as a starting point for drug discovery: natural selection has optimized many of them to bind to specific targets, creating a bias towards biologically relevant compounds that is absent in synthetic libraries. As many as half of all drugs are derived from natural products, suggesting they are a rich source for drug-discovery research.
While natural products can be useful leads for new drugs, finding and collecting enough material to test can be a challenge. This process can be expensive and haphazard, involving anything from diving under the Antarctic ice to venturing into a mangrove swamp. Unlike an ordered synthetic chemical library, the starting point is an extract—a mixed bag of unknown constituents. If this extract has any therapeutic activity, the active compounds must be purified. As the speakers and Q&A sessions highlighted, these challenges make natural product screening a good candidate for precompetitive collaborations that spread the cost among several interested pharmaceutical companies. Another challenge is that the compounds can have complicated structures that are difficult to synthesize traditionally, but both Carr and Koehn demonstrated how microbial biosynthesis can be optimized to overcome this problem.
The cause of AD in most patients is unknown. What is clear is that parts of the brain become crowded with amyloid plaques and neurofibrillary tangles, and synaptic communication based on the neurotransmitter acetylcholine is deficient. In a minority of cases the disease is heritable, and these patients have mutations in the protein constituents of plaques (amyloid-β, Aβ) or tangles (hyperphosphorylated tau), or in the pathways that process these constituents. Introducing these mutations into mice leads to symptoms that resemble AD in humans, making these animals valuable models of the disease. As Aβ and hyperphosphorylated tau proteins accumulate in plaques and tangles, the brain degenerates; this correlation is suspected to reflect a causal relationship. The search is on for compounds that prevent or shrink plaques and tangles or counteract their effects.
Bonnie M. Davis of Synaptec began the case study presentation by reviewing her work to spearhead galantamine (a compound from the snowdrop plant Galanthus nivalis) as a treatment for mild to moderate AD. Galantamine acts in two ways: it inhibits the enzyme that degrades acetylcholine and it promotes target neurons' responses to the neurotransmitter by binding to membrane receptors. This binding makes the smaller amount of acetylcholine in the brains of AD patients more effective, alleviating some of the symptoms of the disease and reducing mortality.
Strategies targeting tau attempt to reduce the number of neurofibrillary tangles, which contain hyperphosphorylated tau, or to compensate for what tau normally does but cannot do when it is ensnared in those tangles. Chad Dickey from the University of South Florida presented evidence that myricanol, a compound found in bayberry extracts (from the Myrica cerifera plant), can reduce the level of tau in cells. The hope is that this work will create a starting point to develop—by further chemical modification—drugs that only target the aberrant forms of the protein that are present in neurofibrillary tangles.
Gabriela Chiosis from Memorial Sloan-Kettering Cancer Center described another strategy. Rather than aiming directly at hyperphosphorylated tau, she is attempting to enhance cellular "housekeeping" functions that can eliminate neurofibrillary tangles in neurons. Geldanamycin, found in the bacteria Streptomyces hygroscopicus, inhibits a protein called Hsp90. This protein both turns off a cellular program that can clear tangles and seems to stabilize hyperphosphorylated tau; inhibiting Hsp90 with geldanamycin increases the clean-up of tangles and destabilizes the aberrant form of tau. But geldanamycin will never be a drug: it is poorly soluble, toxic, and not brain permeable. Chiosis has developed new compounds that inhibit Hsp90 but avoid these problems. Experiments in a mouse model of AD show promising results: good brain permeability, no toxicity, less hyperphosphorylated tau, and improved memory.
Kurt R. Brunden from the University of Pennsylvania presented an alternative drug-development model. Usually, tau binds to microtubules to stabilize them, but when tau is hyperphosphorylated (as in AD) it falls off. Under normal conditions, microtubules form rail-like structures inside neurons, serving as conduits for the transport of substances up and down the length of axons. When microtubules lose tau they break apart, making efficient transport in neurons impossible and causing axons to degenerate. Brunden's approach is to use drugs that stabilize microtubules, keeping the neuron's transport system working. Epothilone D (EpoD), a compound originally identified in the soil bacterium Sorangium cellulolus, has this effect. It can reach the brain, making it a good drug candidate. EpoD is effective for both preventing and reverting axonal degeneration and cognitive decay in mouse models of AD and is now in phase Ib clinical trials.
EpoD reverses nerve degeneration in a mouse model of Alzheimer's disease. Top left: a dystrophic (degenerated) axon in the optic nerve. Bottom left: the number of dystrophic axons in a mouse model with symptoms of AD (PS19) returns to normal (WT) when treated with Epo D (at two doses) but not when treated with a solution without the drug (VEH). Right: EpoD reverses a decrease in axon microtubule density in an AD mouse model. Microtubules function as rails that allow transport within the neuron and their degeneration is believed to cause the axonal dystrophy. (Image courtesy of Kurt R. Brunden)
Salvatore Oddo from the University of Texas Health Science Center at San Antonio moved the focus of the meeting from tau to Aβ, delving into the effects of inhibiting a signaling protein called the mammalian target of rapamycin (mTOR). When mTOR is active it can induce cell growth and inhibit autophagy (a process by which cells degrade internal components). In a mouse model of the disease, Aβ accumulation leads to an increase in mTOR activity. Rapamycin, a compound originally discovered in Streptomyces hygroscopicus soil bacteria collected on Easter Island, inhibits mTOR. A mouse model of AD had less amyloid plaques and hyperphosphorylated tau in the brain after rapamycin administration, as well as improved motor activity and improved ability to learn and remember tasks. This suggests that increased activity of mTOR leads to some symptoms of AD, making this protein a potential drug target. Rapamycin is an immunosuppressant drug approved by the U.S. Food and Drug Administration (FDA), but it can have serious side effects. Nevertheless, it is possible that with an intermittent schedule these side effects could be minimized, making rapamycin a potential drug for AD.
In a mouse model of AD, there is a significant accumulation of amyloid-β (Aβ) plaques in the brain (CTL). Rapamycin inhibited accumulation of plaques when given prophylactically to mice from their second month of life (Rapa 2-18), but not when given to 3- to 15-month-old animals, because the disease has already progressed too far (Rapa 15-18). The brown spots in the top two rows and the green in the bottom row represent amyloid plaques. (Image courtesy of Salvatore Oddo)
Jerold Chun from the Scripps Research Institute shifted the discussion to multiple sclerosis (MS), an autoimmune neurodegenerative disease. Chun related the successful story of fingolimod, a lipid derived from fungal metabolites which was approved by the FDA in 2012 as the first oral treatment for relapsing forms of MS. While the drug was originally thought to act exclusively through a receptor on cells of the immune system, it also seems to have direct effects on the brain, reducing atrophy in MS patients. It is an open question whether similar drugs hold therapeutic potential for AD.
The day ended with a talk by Giulio M. Pasinetti of Mount Sinai School of Medicine. Pasinetti discussed the potential beneficial effects of polyphenolic compounds found in red wine. In mouse models of AD, consumption of moderate amounts of wine or a monomeric polyphenolic extract from the wine enhances learning and reduces Aβ. Recently, his lab has focused on 3′-O-methyl-epicatechin-5-O-β-glucuronide, which enhances neurotransmission and synaptic plasticity in brain slices from a mouse model of AD and can be readily absorbed by the brain. It is still unknown whether this is the active compound. If so, it could represent an avenue for drug development.
The meeting demonstrated the potential for developing drugs from natural products for Alzheimer's disease. While these products may be challenging to find and screen for biological activity, history suggests that valuable drug candidates may lurk in unexpected places.
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Presentations available from:
Kurt R. Brunden, PhD (University of Pennsylvania)
Grant J. Carr, DPhil (AMRI)
Gabriela Chiosis, PhD (Memorial Sloan-Kettering Cancer Center)
Jerold Chun, MD, PhD (The Scripps Research Institute)
Chad Dickey, PhD (University of South Florida)
Howard Fillit, MD (Alzheimer's Drug Discovery Foundation)
Frank E. Koehn, PhD (Pfizer)
David J. Newman, PhD (National Cancer Institute, NIH)
Salvatore Oddo, PhD (University of Texas Health Science Center)
Giulio M. Pasinetti, MD, PhD (Mount Sinai School of Medicine)
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