Gilbert M. Rishton, PhD
Founder and Director
gilbert.rishton@csuci.edu
April, 2005
Alzheimer's disease is a neurodegenerative disorder characterized by dementia and progressive brain wasting. Among Americans who are 65 years of age, 1-in-10 people suffer from the disease. At 85 years of age the proportion of Alzheimer’s sufferers increases dramatically to 1-in-2 people. The world-wide demographic foretells a graying population and a staggering increase in the number of geriatric Alzheimer’s patients. Alzheimer's disease currently claims over 12 million victims. Given the geriatric demographic, Alzheimer’s disease will become tragically common. It is estimated that by the year 2020 up to 30 million people will be affected by this devastating disorder and by the year 2050 the number could increase to 45 million around the world.
Artist charts his slide into dementia, Galerie Beckel Odille Boicos, Paris.
Six self-portraits by artist William Utermohlen chronicle his experience with Alzheimer's disease.
Utermohlen was diagnosed at the age of 60.
The first in this series (top left) was painted in 1996, just prior to diagnosis.
By David Derbyshire (29/06/2001) © Copyright of Telegraph Group Limited 2005
There is currently no cure for Alzheimer’s disease. The available drug treatments are palliative cognition enhancing agents that inhibit acetylcholine esterase (AChE) so as to maintain high levels of the key neurotransmitter acetylcholine (ACh). These drugs do not address the mechanism of Alzheimer’s disease and so cannot stem the devastating neurodegeneration that results. However, there is much to be learned from the chemical structures and the physiochemical properties of these approved drugs. They possess the properties that enable oral administration and efficacy at a central nervous system therapeutic target. The Alzheimer’s Institute intends to investigate novel drug candidates of this type that will address Alzheimer’s disease at it’s mechanistic origins for the treatment and prevention of neurodegeneration.
The effective Alzheimer’s disease therapies of the future will be small molecule drugs formulated as pills and capsules for oral administration. The Alzheimer’s Institute intends to discover new lead molecules to enable the development of orally administered Alzheimer’s disease drugs.
Our intention is to prepare a high quality collection of “chemically conditioned” extracts derived from natural sources. Our proprietary chemical conditioning methodology will produce leadlike and druglike molecules for biological testing. Included in our archived collection will be conditioned extracts of the ethnobotanical herbal remedies that have been used for hundreds of years to treat dementias, including Alzheimer’s disease. Our chemically conditioned extracts will be fractionated and formatted in 96-well plate array for biological testing at Alzheimer’s disease-relevant receptors and enzymes.
We intend also to study the effect of our conditioned extracts on the propensity of stem cells to differentiate into neuronal cells. In this way we will benfit from recent advances in the understanding of stem cells and pursue the development of orally administered neuroregenerating agents.
Our archived collection of chemically conditioned extracts will be made available for biological testing by our partners and collaborators in academia and the pharmaceutical industry.
The pharmaceutical industry has largely abandoned the practice of screening natural extracts to find new drug leads. This is not because natural extracts have become any less valuable, or because they now contain less interesting and less structurally diverse compounds. The problem is that for the last 15 years we have depended on highly sensitive biochemical assays for our first tier drug screening efforts. These sensitive biochemical assays are ineffective for the screening of natural extracts because the extracts tend to contain non-druglike chemically reactive compounds and various high molecular weight polymeric materials that cause artifact data in biochemical assays and undermine our search for new drug leads.
Compound quality is a very important consideration in the early stages of a drug discovery program when a project team will commonly assay hundreds of thousands of chemical compounds in the search for a new drug lead. High quality drug leads are vital for the success of drug development and this is particularly true in the search for central nervous system agents such as Alzheimer’s disease drug leads. The Alzheimer’s Institute proprietary chemical conditioning of natural extracts will destroy chemically reactive false positives and create novel and chemically stable ligands suitable for testing in sensitive biological assays. Our chemical conditioning methods, used in combination with certain enzymatic treatments, will also cleave polymeric materials such as cellulose, protein, peptides, and nucleosides to create chemically stable, low molecular weight fragments of these biomolecules. The conditioned extracts so obtained will be pre-fractionated for biological screening. The chemically conditioned and pre-fractionated leadlike and druglike materials will enable high quality data generation at Alzheimer’s disease-relevant biological targets.
The advantages of chemical conditioning of common natural extracts: The Alzheimer’s Institute proprietary method for chemical conditioning and pre-fractionation of natural extracts promises to create a revolution in the biochemical screening of commonly available extracts. The following advantages of this methodology will provide significant leverage for success in drug discovery.
The current state-of-the-art in analytical methods is significantly superior to that of the methods used during the classical heyday of natural products extraction and screening. Spectroscopic methods have become so advanced that the daily structural characterization of novel chemical compounds of unknown structure is an altogether practical proposal. Even x-ray crystallography and the co-crystallization of small molecule ligands in the binding sites of their protein targets have become well-developed methods and even parallelized processes. It would seem that the screening of natural and un-natural compounds of unknown structure is now, more than ever, a practical and promising proposal for the discovery of new drug leads. Given an extensive and replenishable collection of leadlike and druglike compounds, one might expect to discover and characterize novel drug leads with relative facility.
Supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC) offer a fully-integrated platform for the development of an archived collection of chemically conditioned and pre-fractionated extracts for biological testing. Supercritical carbon dioxide blended with small amounts of organic co-solvent has been used for some time to extract various plants (for example; ginkgo biloba, ginseng, peony, and kava) to provide “nutraceuticals” on multi-kilogram scale. SFE provides an ideal extraction medium for leadlike and druglike small molecules. Importantly, the use of large quantities of organic solvent is avoided and so the need for evaporation of high volumes of solvent and the generation of hazardous organic solvent waste is minimized.
Extracts obtained by SFE, either before or after chemical conditioning, can be fractionated efficiently using a supercritical mobile phase employing preparative SFC technology. Ideally, the fractionated eluent would be directly dry-plated into a 96-well plate archive format. The SFC process requires no evaporation of large volumes of liquid phase as in HPLC. One can envision the development of a seamless process employing SFE, chemical conditioning, and fractionation by SFC leading to direct plating of fractions in 96-well format for biological screening.
The practicality and scalability of the chemical conditioning, extraction, and fractionation method will become most apparent when a biologically active drug lead is discovered in a given screening program. The active compound will likely be leadlike and druglike. The source of the natural extract will likely be common and readily obtainable on multi-kilogram scale. Repetition of our proprietary conditioning regimen on this large scale, followed by pilot scale SFE and preparative SFC procedures will replenish the supply of the precious new drug lead. It is not unreasonable to propose that we might obtain multi-gram quantities of the pure compound in this way with no requirement for difficult collection or expensive and time consuming re-synthesis.
Pilot scale supercritical fluid extractor
Ultimately, our goal is to develop an archived collection of conditioned extracts containing leadlike and druglike compounds for screening in Alzheimer’s disease-relevant biological assays to discover new Alzheimer’s drug leads. We intend to investigate commonly available natural materials as well as the ethnobotanical herbal remedies that have been used traditionally to treat dementias, including Alzheimer’s disease. We will create value by protecting new intellectual property in the form of composition-of-matter patent applications. The Alzheimer’s Institute will seek to out-license intellectual property to pharmaceutical industry partners so as to accelerate the development of our new drug leads toward human trials for the treatment of Alzheimer’s disease. Additionally, we will aggressively communicate the structure-activity data we generate in our discovery programs for the information of the greater Alzheimer’s disease research community.
Working with the Departments of Biology and Chemistry at California State University, Channel Islands, the Alzheimer’s Institute intends to provide educational opportunities for the development of student scientists in the form of applied drug discovery research projects focused on a very worthy cause. Working with our pharmaceutical industry partners, we intend to enable and accelerate the development of drug candidates that might address the unmet medical need of Alzheimer’s patients worldwide.
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