REPRINTED FROM THE NEW YORK TIMES
Housed in a row of white freezers in a nondescript laboratory at the Johns Hopkins University School of Medicine in Baltimore are more than 3,000 of the estimated 10,000 drugs known to medicine. There is no sign on the door to indicate that this is perhaps the largest public drug library available to researchers interested in finding new uses for old and often forgotten drugs.
Already, researchers have used the library to discover that itraconazole, a drug used for decades to treat toenail fungus, may also inhibit the growth of some kinds of tumors and may forestall macular degeneration. Another drug, clofazimine, used more than a century ago to treat leprosy, may be effective against autoimmune disorders like multiple sclerosis and psoriasis.
“It takes 15 years and costs close to a billion dollars to develop a new drug,” said Jun O. Liu, professor of pharmacology and director of the Johns Hopkins Drug Library. “Why not start with compounds that already have proven safety and efficacy?”
He and his colleagues have been building the collection since 2002 and hope to have it complete by 2011. They acquire the drugs through donations, purchases and sometimes lab synthesis. And they will send researchers a complete set — minuscule amounts of every drug in the library — for $5,000, which covers the cost of shipping and replenishment.
Since the toenail and leprosy drugs are approved for use in the United States and are no longer under patent protection, clinical trials to test their new uses are either under way or close to regulatory approval, Dr. Liu said.
Drugs still under patent protection are more complicated; patent holders seldom allow independent research on alternative uses. “The drug companies haven’t been too keen on helping us,” Dr. Liu said.
There are other drug libraries, both commercial and noncommercial. Commercial suppliers offer considerably fewer drugs than Johns Hopkins (though they may have medicines it does not), and they charge much more. Noncommercial drug libraries include those at the National Institutes of Health; the University of California, San Francisco; and McMaster University in Hamilton, Ontario. But they will usually not send drugs to unaffiliated researchers. And like the commercial libraries, their holdings are smaller and composed largely of compounds from Hopkins.
Regardless of the source, researchers typically order copies of entire collections rather than individual drugs they think may work in their experiments.
“We’ve found drugs that are active in ways no one would have ever hypothesized,” said Marc G. Caron, a professor of cell biology at Duke who is using the Johns Hopkins library to find drugs that might quell the cravings of substance abusers.
Testing of these compounds has become much easier in recent years as a result of an automated technology called H.T.S., for high-throughput screening. The drugs are dissolved in a solution and stored in rectangular, compartmented plates reminiscent of ice trays; they can then be delivered to researchers for testing of their efficacy against various diseases, or disease mechanisms like inflammation.
Computerized droppers, plate agitators and microscope image readers can now accomplish in days what it once took bench scientists years to do.
Although H.T.S. has been around for at least a decade, it is just within the last five years that the technology has been widely available. Previously, only big pharmaceutical companies could afford to screen thousands of compounds; now more public and academic institutions are doing so, and their emphasis tends to be on rediscovering or tweaking the chemical structure of old drugs rather than developing new ones.
“The instrumentation to do sophisticated, large-scale screening of drugs has gotten significantly better and cheaper,” said Michelle Arkin, associate director of the Small Molecule Discovery Center at U.C. San Francisco.
Some institutions, like McMaster in Ontario and Rockefeller University in New York City, allow outside researchers to use their H.T.S. facilities for $10,000 to $20,000, depending on the complexity of the project.
Access to such facilities has increased demand for compounds, particularly already approved and off-patent drugs, to analyze. Johns Hopkins and commercial suppliers report a surge in orders over the last two years — because there are more H.T.S. laboratories, they said, and because of efforts to find cheaper therapies against third world scourges like malaria and tuberculosis.
“Old drugs are the low hanging fruit in terms of finding safe and inexpensive treatments for these diseases,” said Carl Nathan, chairman of microbiology at Weill Cornell Medical College in New York. Dr. Nathan receives plates of drugs from Johns Hopkins as well as commercial suppliers and does high-throughput screening at Rockefeller, which has a partnership with Weill.
“I’m addicted to it,” he said.
Saturday, May 30, 2009
Sunday, May 10, 2009
Researchers aim for rare treatment of macular degeneration
Friday, May 1, 2009
Researchers aim for rare treatment of macular degeneration
By Marc Songini
One of the most prevalent eye diseases is age-related macular degeneration, affecting millions in the United States, and there are few if any cures, or even approved treatments, say experts. That makes the work of a group of local researchers developing an implanted treatment particularly vital.
The AMD ailment takes two forms: One is “wet” and involves blood vessels and has limited treatments, including Lucentis, a drug from San Francisco-based Genentech Inc. (now part of Swiss firm Roche). The other is “dry” and occurs when light-sensitive cells malfunction. An estimated 15 million Americans have AMD.
For the 10 percent to 20 percent of AMD patients that have the wet form, the treatments are “reasonably effective,” said Paul Ashton, president and CEO of Watertown-based pSivida Corp., which develops eye treatments. “We have nothing for the 80 percent to 90 percent who have the dry form.” In part, this is because big pharma didn’t realize the huge market for eye treatments until about a decade ago, he said. Additionally, “Getting drugs into the eye without getting very high levels of drug everywhere else is very hard,” noted Ashton.
For dry AMD, in particular, there’s “a huge unmet need and a huge market,” said Emmett Cunningham, a partner with Cambridge-based Clarus Ventures LLC, a life sciences investment company. In part, said Cunningham, a doctor and eye expert based in Clarus’ South San Francisco office, this is because dry AMD is “complex,” and there is no one easily discerned cause. Also, there are no reliable animal models for testing.
“You’d have to take a big bet to get human proof of concept data,” he said. A venture capital firm would be prone to waiting till a dry AMD startup was in the Phase 2 or Phase 3 stage before investing the $20 million to move toward full approval.
However, one research team based at Boston College and the University of Massachusetts Medical School in Worcester is trying to solve the problems of AMD and other eye diseases by creating nano-structured retinal implants. These are tiny devices placed in the eye to take the place of the malfunctioning rods and cones in the retina, explained Michael Naughton, a professor of physics at BC, whose team is working on the nanotechnology of the implant.
“The implant is designed to reconnect to the surviving cell circuitry and provide the electronic stimulus formerly provided by the rods and cones,” said Naughton. Ideally, these implants could have a form factor similar to contact lenses. They would be widely available, although requiring retinal surgery. “Until such a time as genetic engineering can cure or regenerate rods and cones, these artificial retinas could provide a viable path to restoring vision.” Potentially, the market is worth hundreds of millions of dollars annually, he estimated.
Currently, he estimates that he needs $42 million to pay for the prototype and the animal and human studies over the next 18 months. He said there are no implants on the market for consumer use at this time, though a number are in development.
Cunningham noted that for an investor, implants are an interesting area, but the key is getting compelling data that the technical risks associated with the device have been met, because it requires surgical implantation. Also, a startup must demonstrate the size of the market is big enough related to the cost of the device, he said.
Other firms working to treat AMD and other eye ailments include Lincoln, R.I.-based Neurotech Pharmaceuticals Inc., whose lead candidate NT-501 is an intraocular implant made of genetically modified human cells. In March, it released Phase 2 exploratory study data that indicated positive results in AMD treatment, with no “serious adverse events,” said Ted Danse, president and CEO of Neurotech.
Also, pSivida’s drug Iluvien is in Phase 2 trials for both forms of AMD, said Ashton. And New Haven, Conn.-based Optherion Inc. is developing a diagnostic service and drug platform for AMD. By year’s end, Optherion plans to file an independent new drug application (IND) submission to the U.S. Food and Drug Administration for its drug, said Colin Foster, CEO and president.
For the past several years, Bedford-based Resolvyx Pharmaceuticals Inc. has been evaluating its Resolvin inflammation control drug’s effectiveness against AMD, as well.
Researchers aim for rare treatment of macular degeneration
By Marc Songini
One of the most prevalent eye diseases is age-related macular degeneration, affecting millions in the United States, and there are few if any cures, or even approved treatments, say experts. That makes the work of a group of local researchers developing an implanted treatment particularly vital.
The AMD ailment takes two forms: One is “wet” and involves blood vessels and has limited treatments, including Lucentis, a drug from San Francisco-based Genentech Inc. (now part of Swiss firm Roche). The other is “dry” and occurs when light-sensitive cells malfunction. An estimated 15 million Americans have AMD.
For the 10 percent to 20 percent of AMD patients that have the wet form, the treatments are “reasonably effective,” said Paul Ashton, president and CEO of Watertown-based pSivida Corp., which develops eye treatments. “We have nothing for the 80 percent to 90 percent who have the dry form.” In part, this is because big pharma didn’t realize the huge market for eye treatments until about a decade ago, he said. Additionally, “Getting drugs into the eye without getting very high levels of drug everywhere else is very hard,” noted Ashton.
For dry AMD, in particular, there’s “a huge unmet need and a huge market,” said Emmett Cunningham, a partner with Cambridge-based Clarus Ventures LLC, a life sciences investment company. In part, said Cunningham, a doctor and eye expert based in Clarus’ South San Francisco office, this is because dry AMD is “complex,” and there is no one easily discerned cause. Also, there are no reliable animal models for testing.
“You’d have to take a big bet to get human proof of concept data,” he said. A venture capital firm would be prone to waiting till a dry AMD startup was in the Phase 2 or Phase 3 stage before investing the $20 million to move toward full approval.
However, one research team based at Boston College and the University of Massachusetts Medical School in Worcester is trying to solve the problems of AMD and other eye diseases by creating nano-structured retinal implants. These are tiny devices placed in the eye to take the place of the malfunctioning rods and cones in the retina, explained Michael Naughton, a professor of physics at BC, whose team is working on the nanotechnology of the implant.
“The implant is designed to reconnect to the surviving cell circuitry and provide the electronic stimulus formerly provided by the rods and cones,” said Naughton. Ideally, these implants could have a form factor similar to contact lenses. They would be widely available, although requiring retinal surgery. “Until such a time as genetic engineering can cure or regenerate rods and cones, these artificial retinas could provide a viable path to restoring vision.” Potentially, the market is worth hundreds of millions of dollars annually, he estimated.
Currently, he estimates that he needs $42 million to pay for the prototype and the animal and human studies over the next 18 months. He said there are no implants on the market for consumer use at this time, though a number are in development.
Cunningham noted that for an investor, implants are an interesting area, but the key is getting compelling data that the technical risks associated with the device have been met, because it requires surgical implantation. Also, a startup must demonstrate the size of the market is big enough related to the cost of the device, he said.
Other firms working to treat AMD and other eye ailments include Lincoln, R.I.-based Neurotech Pharmaceuticals Inc., whose lead candidate NT-501 is an intraocular implant made of genetically modified human cells. In March, it released Phase 2 exploratory study data that indicated positive results in AMD treatment, with no “serious adverse events,” said Ted Danse, president and CEO of Neurotech.
Also, pSivida’s drug Iluvien is in Phase 2 trials for both forms of AMD, said Ashton. And New Haven, Conn.-based Optherion Inc. is developing a diagnostic service and drug platform for AMD. By year’s end, Optherion plans to file an independent new drug application (IND) submission to the U.S. Food and Drug Administration for its drug, said Colin Foster, CEO and president.
For the past several years, Bedford-based Resolvyx Pharmaceuticals Inc. has been evaluating its Resolvin inflammation control drug’s effectiveness against AMD, as well.
Sunday, May 3, 2009
Functional annotation of the human retinal pigment epithelium transcriptome
Functional annotation of the human retinal pigment epithelium transcriptome
To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE), the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy human donor eyes (aged 63-78 years) were laser dissected and used for 22K microarray studies (Agilent technologies).
Data were analyzed with Rosetta Resolver, the web tool DAVID and Ingenuity software.
Results: In total, we identified 19,746 array entries with significant expression in the RPE. Gene expression was analyzed according to expression levels, interindividual variability and functionality.
A group of highly (n=2,194) expressed RPE genes showed an overrepresentation of genes of the oxidative phosphorylation, ATP synthesis and ribosome pathways. In the group of moderately expressed genes (n=8,776) genes of the phosphatidylinositol signaling system and aminosugars metabolism were overrepresented.
As expected, the top 10 percent (n=2,194) of genes with the highest interindividual differences in expression showed functional overrepresentation of the complement cascade, essential in inflammation in age-related macular degeneration, and other signaling pathways. Surprisingly, this same category also includes the genes involved in Bruch's membrane (BM) composition.
Among the top 10 percent of genes with low interindividual differences, there was an overrepresentation of genes involved in local glycosaminoglycan turnover.
Conclusions: Our study expands current knowledge of the RPE transcriptome by assigning new genes, and adding data about expression level and interindividual variation.
Functional annotation suggests that the RPE has high levels of protein synthesis, strong energy demands, and is exposed to high levels of oxidative stress and a variable degree of inflammation. Our data sheds new light on the molecular composition of BM, adjacent to the RPE, and is useful for candidate retinal disease gene identification or gene dose-dependent therapeutic studies.
Author: Judith C Booij, Simone van Soest, Sigrid MA Swagemakers, Anke HW Essing, Annemieke JMH Verkerk, Peter J van der Spek, Theo GMF Gorgels and Arthur AB Bergen
Credits/Source: BMC Genomics 2009, 10:164
To determine level, variability and functional annotation of gene expression of the human retinal pigment epithelium (RPE), the key tissue involved in retinal diseases like age-related macular degeneration and retinitis pigmentosa. Macular RPE cells from six selected healthy human donor eyes (aged 63-78 years) were laser dissected and used for 22K microarray studies (Agilent technologies).
Data were analyzed with Rosetta Resolver, the web tool DAVID and Ingenuity software.
Results: In total, we identified 19,746 array entries with significant expression in the RPE. Gene expression was analyzed according to expression levels, interindividual variability and functionality.
A group of highly (n=2,194) expressed RPE genes showed an overrepresentation of genes of the oxidative phosphorylation, ATP synthesis and ribosome pathways. In the group of moderately expressed genes (n=8,776) genes of the phosphatidylinositol signaling system and aminosugars metabolism were overrepresented.
As expected, the top 10 percent (n=2,194) of genes with the highest interindividual differences in expression showed functional overrepresentation of the complement cascade, essential in inflammation in age-related macular degeneration, and other signaling pathways. Surprisingly, this same category also includes the genes involved in Bruch's membrane (BM) composition.
Among the top 10 percent of genes with low interindividual differences, there was an overrepresentation of genes involved in local glycosaminoglycan turnover.
Conclusions: Our study expands current knowledge of the RPE transcriptome by assigning new genes, and adding data about expression level and interindividual variation.
Functional annotation suggests that the RPE has high levels of protein synthesis, strong energy demands, and is exposed to high levels of oxidative stress and a variable degree of inflammation. Our data sheds new light on the molecular composition of BM, adjacent to the RPE, and is useful for candidate retinal disease gene identification or gene dose-dependent therapeutic studies.
Author: Judith C Booij, Simone van Soest, Sigrid MA Swagemakers, Anke HW Essing, Annemieke JMH Verkerk, Peter J van der Spek, Theo GMF Gorgels and Arthur AB Bergen
Credits/Source: BMC Genomics 2009, 10:164
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