April 25, 2002
Note: The following report was prepared by the National Institute of Neurological Disorders and Stroke (NINDS).
Scientists, government representatives, and members of patient groups met in Washington, D.C. on April 7 -8, 2002, to discuss the initial phase of an intensive, large-scale effort to identify FDA-approved drugs with potential for treating amyotrophic lateral sclerosis (ALS), Huntington's disease, and other neurodegenerative diseases. The meeting allowed investigators to compare their progress to date, to review and decide on a method for analyzing the data being generated by the massive effort, and to discuss the next steps that will allow them to move toward future clinical trials.
The unusual drug-screening effort was sponsored by a consortium of four organizations: the Hereditary Disease Foundation (HDF), the Huntington's Disease Society of America (HDSA), The ALS Association (ALSA), and the National Institute of Neurological Disorders and Stroke (NINDS). Investigators from 26 laboratories took part in the initial 6-month, $1.3 million project, which tested 1,040 compounds using 29 different assays, or tests. The assays used in this study identified possible effects of the drugs on cell death, protein aggregation, or other processes that have been linked to neurodegenerative diseases. Almost all of the tested compounds had previously been approved by the FDA for use in treating other disorders. Several other compounds, such as nutritional supplements and research chemicals, were included in the screen in order to provide reference points.
"This is the first time that so many investigators have collaborated on a drug screening project," says Jill Heemskerk, Ph.D., the NINDS program director for this study. The large number of investigators who took part in this collaborative research effort resulted in compounds being tested in many different model systems simultaneously. This greatly reduced the time needed for the initial phase of the study. All of the investigators agreed to share their data prior to receiving funding for the study.
The screening program reflects NINDS' strong commitment to research that translates the results of basic science into potential new therapies. It was developed in response to recommendations from an NINDS-sponsored meeting on high throughput (rapid) screening for ALS drug candidates that took place in April 2000 and from the NINDS Strategic Planning Panel on Neurodegeneration. Both of these efforts included members of the organizations that participated in the drug screening consortium. NINDS also has issued a Request for Applications to develop new assays for drug screening and genetics, and it plans to award a contract for a high throughput drug screening facility for neurodegenerative diseases this fall.
"The participation of the HDSA, the HDF, and the ALSA was vital to this effort," says Dr. Heemskerk. These organizations all had drug screening and development programs before this effort began, and they had established groups of investigators who they encouraged to take part in this study. They also supported the development of many of the assays used in this screening program.
While drug companies frequently conduct rapid drug-screening programs that examine thousands of compounds at a time, this effort is unique in that it was publicly funded and targeted FDA-approved drugs. FDA-approved drugs have significant advantages compared to newly identified compounds because they are already on the market and have undergone years of testing in humans. This means that they could be immediately available for testing in human clinical studies if the data from the drug screen look promising.
Many drugs have potentially useful effects that go beyond their original use, says Dr. Heemskerk. For example, aspirin was originally used as a pain reliever, but it has now been shown to reduce the risk of heart disease and stroke as well. While the collection of compounds used in this study is much smaller than the number of compounds usually tested by pharmaceutical companies, it is chemically diverse. This made it plausible that one or more of the drugs might be effective against neurodegenerative disorders.
Investigators participating in the project had existing grants from the NINDS or one of the other three organizations. They received special supplemental grants to test the collection of compounds in models for Huntington's disease, ALS and other neurodegenerative disorders. All of the compounds tested in this study were provided to investigators in pre-assembled "kits" by a company called MicroSource Discovery Systems, Inc. Using this common screening kit allowed the drugs to be tested faster than if investigators had to assemble the collections individually. It also made the comparisons of data from different labs more reliable, because the chemical formulation and concentration of each compound was the same in each kit. The investigators were "blinded" to the identities of the different compounds until after they completed the tests.
Because of the short time frame for the initial phase of testing, most of the tests took place in in vitro models of disease, such as cultured cells. A few researchers tested the compounds in fast-growing organisms such as worms, fruit flies, and zebrafish with characteristics that modeled possible mechanisms for neurodegenerative disease. Researchers tested the effects of the drugs on cell dysfunction and death, on gene activity, and on aggregation, or "clumping," of proteins. These processes have all been linked to neurodegenerative disease in previous studies.
As the data collection is completed, analyzed, and re-tested for validity, the consortium plans to create a database with results from all of the investigators. This database will ultimately become a tool for the larger scientific community as well as for the investigators who participated in this study. The compiled data will be analyzed by a statistician who will help identify compounds that might be good candidates for further testing and development. For example, drugs that show statistically significant activity in multiple tests may be especially promising candidates for tests in animal models.
The data from the initial phase of the study will also be submitted for publication in a scientific journal once they are analyzed.
More research is needed before any of the tested compounds can be considered for clinical trials. However, NINDS is hopeful that the data collected during the initial phase of this program could ultimately lead to new treatments for ALS, Huntington's, and other neurodegenerative disorders, according to Dr. Heemskerk. The effort also yielded information that can help evaluate the usefulness of the different assays for further drug development efforts, she notes. This information may help to encourage future large-scale drug screening programs to identify treatments for neurological diseases.