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Drug Screening for Ataxia-Telangiectasia

Drug Screening for Ataxia-Telangiectasia
Hyatt Regency Hotel, Bethesda, MD
October 8, 2004


The National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Diseases (ORD) at NIH along with the A-T Children's Project. (A-TCP) co-sponsored this workshop. This scientific workshop was organized by Dr. Danilo A. Tagle (NINDS), Dr. Jill Heemskerk (NINDS), and Dr. Cynthia J. Rothblum-Oviatt, (A-TCP).

Ataxia-telangiectasia (A-T) is an autosomal recessive disease with a pleiotropic phenotype. A-T patients exhibit cerebellar degeneration leading to neuromotor dysfunction, immunodeficiency, chromosomal instability, progeria, cancer predisposition and acute sensitivity to ionizing radiation. The gene mutated in A-T, ATM (for AT-mutated), had been cloned and found to have ionizing radiation and oxidative stress-inducible protein kinase activity. Immediately after double-strand breaks, ATM activity is enhanced and it phosphorylates a plethora of substrates, such as p53 and its ubiquitin ligase, Mdm2, Nbs1, Brca1, Chk2, Rad17 and SMC1. These ATM substrates act on one or more of the cell cycle checkpoints.

The NINDS has established a high throughput drug screening (HTS) facility for neurodegenerative diseases at the Southern Research Institute in Birmingham, Alabama. In January 2003, the NINDS and the A-TCP held a workshop to identify assays that might prove amenable for HTS, in order to take advantage of this technology and the newly established NINDS facility. The objective of the workshop was to identify potentially therapeutic lead compounds for A-T. That workshop identified two biological cell-based assays that might be suitable for scaling up and for transfer to the automated devices for HTS. Unfortunately, this proved not to be the case as these assays could not be transferred appropriately to HT screening conditions.

Thus the purpose of this follow-up workshop was to convene A-T researchers and assay development experts from industry and academia to consider alternative approaches for assay development. The objective of this workshop was

  • To define the best approaches for development and validation of a cell-based assay for HTS
  • To determine the feasibility of using target-based assays or transcription read-through assays that might be amenable for medium or high throughput screening for A-T.

The immediate goals of the workshop included:

  • To provide an opportunity for scientists from academia and industry to come together and define the issues and feasibility of an assay system amenable for high throughput drug screen as it relates to A-T
  • To identify resources, such as cell lines, animal models, and antibodies, that can be used to develop a HTS assay for A-T
  • To foster collaborations amongst the scientists, and to further interactions and partnerships between NIH and the A-TCP


During the workshop various assays were presented that might prove suitable for A-T drug screening in a moderate-high throughput format including:
" Mechanism-based assays utilizing FRET or IF
" Phenotype-based assays for cell survival or differentiation
" Transcriptional read-through assays
" Organism-based assays.

Based upon the workshop presentations, it appears that organism-based assays are not ready for HTS at this time. However, certain fly-based assays may be suitable for low-moderate throughput drug screening.

It was noted that cell-based assays (including mechanism-based and phenotype-based assays) tend to be successful in HTS paradigms when they are very robust. The shorter the experimental time course the better, as longer time courses increase the chance of variability in the system. Some variability in these assays can now be addressed using cell-based, high content instruments.

In developing a cell-based assay for A-T, investigators should consider the primary goal of drug screening for this disease, which was considered by the participants to be prevention of neurodegeneration. An important open question remaining from the workshop was: Do we know enough about the cause of the neurodegeneration in A-T and the biology of ATM to design truly effective cell-based screening assays?

Given the current state of our knowledge, it was felt that, although there may be certain disadvantages to utilizing mechanism-based assays as the primary screen, perhaps both mechanism-based and phenotype-based, survival assays should be pursued. It was also noted that for any cell-based screen utilizing A-T cells, counter screens would have to be performed using normal, control cells.

In terms of the libraries to be used in a drug screen for A-T, participants felt that FDA-approved compounds should be included in a primary screen.

From the perspective of the NINDS HTS facility, exploratory assay development has proven too cumbersome and expensive under the contract. Therefore, it is important that investigators carry out the necessary assay development and validation steps before the assay proposals are submitted for consideration for screening. A similar policy has been adopted by the NIH Roadmap HTS enterprise that is currently being established.

NIH has new programs to support assay development by investigators, and a list of these is found below. Through grants funded under these programs, investigators will be able to develop assays with potential for adaptation to a HTS platform. Then the investigators will need to work with NIH centers, their respective institutions, or in collaboration with an interested drug company to transfer the assay to a high throughput screening facility.

NIH Funding Sources for Assay Development for Small Molecule Screens
Updated December 7, 2004

" NINDS Small Research Grant (R03)
Small grants of up to $50,000 per year for two years, intended to support development of a defined resource, such as a screening assay. More information about applying can be found at:

" NINDS Exploratory/Developmental Projects in Translational Research (R21)
Grants of up to $125,000 per year for two years, intended to support early stage therapeutics development projects for neurological disorders, including the development of assays for compound screens.

" NIH Roadmap Assay Development RFA (R03 and R21)
A trans-NIH program to support the development of screening assays in any area of biology and disease. This program is conducted by NINDS as part of the NIH-wide Molecular Libraries Roadmap initiative. The RFA can be found at:

" NIH Program Announcement: Development of Assays for High Throughput Drug Screening (R01)
The purpose of this program announcement is to encourage the use of high throughput small molecule screening for use in both research and drug discovery programs by funding the development of innovative assays that may be adapted for automated screening.  The assays would aim to identify new tools for basic research and promising new avenues for therapeutics development, especially in areas related to the missions of NIDDK, NCI and NIAID.

Drug Screening for Ataxia-Telangiectasia
Hyatt Regency Hotel, Bethesda, MD
October 8, 2004

Sponsored by the NINDS, ORD and the A-T Children's Project

Workshop Objective
To develop one or more practical assay protocols for A-T drug screening.


8:00-8:30 am
Registration and Continental Breakfast
8:30-8:40 am  
Charge to Participants
Danilo Tagle, NINDS
8:40-9:00 am
A-T and ATM: A Current Overview
Yossi Shiloh, Tel Aviv University, Israel
9:00-9:15 am   
What's Been Learned From the Mouse Model of A-T
Peter McKinnon, St. Jude's Childrens Hospital
9:15-9:45 am
Discussion: Gaps in Our Understanding of A-T - The Use of Drug Screening for the Generation of Research Tools
Facilitator: Jill Heemskerk, NINDS
9:45-10:00 am

Cell Based Assays

10:00-10:20 am
Yossi Shiloh, Tel Aviv University, Israel
10:20-10:40 am
Ilan Tsarfaty, Tel Aviv University, Israel
10:40-11:00 am
Bob Abraham, Burnham Institute
11:00-11:20 am
Martin Lavin, Queensland Institute of Medical Research, Australia
11:20-11:40 am
Brendan Price, Dana Farner
11:40-1:10 pm
Discussion: Development and Validation of Cell Based Assays for HTS*
Facilitator: Michael Kastan, St. Jude's Childrens Hospital

*Working lunch during this session

1:10-1:20 pm
1:45 pm

Target Based Assays

1:20-1:40 pm
Wei Zheng and Priya Kunapuli, Merck

Transcription Read-Through Assays

1:40-2:00 pm
David Lawrence, Albert Einstein College of Medicine

Low-Moderate Through-put Assays

2:00-2:20 pm
Mary Morrison (mouse model), Scripps Research Institute
2:20-2:40 pm
Shelagh Campbell (fly model), University of Alberta, Canada
2:40-3:00 pm
Stuart Milstein (C. elegans model), Dana Farber
3:00-3:20 pm
Shuji Kishi (zebra fish), Dana Farber
3:20-3:30 pm
3:30-5:30 pm
Discussion : Prioritization of Assay Protocols
Facilitators: Chris Austin, Jill Heemskerk, Jim Inglese and Danilo Tagle, NIH
5:30 pm


Douglas S. Auld, Ph.D.
Chemical Genomics Center
National Human Genome Research Institute
National Institutes of Health

Christopher P. Austin, M.D.
Chemical Genomics Center
National Human Genome Research Institute
National Institutes of Health

Shelagh D. Campbell, Ph.D., M.Sc.
Department of Biological Sciences
University of Alberta

Thomas M. Fletcher III, Ph.D.
Drug Discovery Division
Southern Research Institute

Richard A. Gatti, M.D.
Department of Pathology
UCLA School of Medicine

Larry Gelbert
Department of Integrative Biology
Eli Lilly and Company

Jill Heemskerk, Ph.D.
Technology Development
National Institute of Neurological Disorders and Stroke, NIH

David E. Hill
Dana Farber Cancer Institute
Harvard Medical School

Jim Inglese, Ph.D.
Biomolecular Screening and Profiling
Chemical Genomics Center
National Human Genome Research Institute
National Institutes of Health

Karl K. Johe, Ph.D.
Neuralstem, Inc.

Carl D. Johnson, Ph.D.
Hereditary Disease Foundation

Michael B. Kastan, M.D., Ph.D.
Division of Hematology
Department of Oncology
St. Jude Children's Research Hospital

Shuji Kishi, M.D., Ph.D.
Harvard Medical School
Cancer Biology and Pathology
Dana Farber Cancer Institute

Priya Kunapuli, Ph.D.
Division of Automated Biotechnology
Merck & Co.

Martin Francis Lavin, B.Sc., Ph.D.
Department of Cancer and Cell Biology
Queensland Institute of Medical Research, Bancroft Centre

David S. Lawrence, Ph.D.
Department of Biochemistry
Albert Einstein College of Medicine

Rod Levine, M.D., Ph.D.
National Heart, Lung, and Blood Institute
National Institutes of Health

Brad A. Margus, M.B.A.
Perlegen Sciences

Peter J. McKinnon, Ph.D.
Genetics and Tumor Cell Biology
St. Jude Children's Research Hospital

Howard T.J. Mount, Ph.D.
Department of Neurology/Medicine
University of Toronto

Tej K. Pandita, Ph.D.
Department of Radiation Oncology
Washington University School of Medicine

Brendan D. Price, Ph.D.
Department of Radiation Oncology
Dana-Farber Cancer Institute

Cynthia J. Rothblum-Oviatt, Ph.D.
A-T Children's Project

Yosef Shiloh, Ph.D.
Human Genetics and Molecular Medicine
University of Tel Aviv
Sackler School of Medicine

Giovanna M. Spinella, M.D.
Office of Rare Diseases
Office of the Director, NIH

Danilo Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke, NIH

Ilan Tsarfaty
Department of Human Microbiology
Sackler Faculty of Medicine
Tel Aviv University

Andreas Wissmann, Ph.D.
NemaRx Pharmaceuticals, Inc.

Wei Zheng, Ph.D.
Automated Biology
Merck and Company


Last Modified April 6, 2011