Charles River Lab, a drug development services company collaborating with the A-T Children’s Project, has succeeded in developing a laboratory test or “assay” to rapidly evaluate thousands of approved drugs to learn if some of them can be repurposed for A-T. Because drugs emerging from the screening process with promising results will have already been approved for other diseases, they should have a faster path to approval for treating A-T patients than a new drug would have.

The A-T Children’s Project has now given the company the green light to proceed to the next phase: running a pilot screen over a two-month period using a highly automated and controlled process. And then, if the pilot screen runs smoothly, the project will advance to a third phase: testing over five thousand compounds to identify drugs that correct a biological problem seen in cells from children with A-T.

Completing the first phase wasn’t easy. The Charles River Lab team had to decide which cellular defect to measure to determine if a drug was having a positive effect. Knowing that cells from A-T children have trouble repairing damaged DNA, they painstakingly developed and fine-tuned a process to grow A-T cells in a dish, treat them with a potentially therapeutic drug, stress them with a DNA-damaging chemical, and then measure the level of a protein that would be expected to increase only if the drug had helped to restore the cells’ DNA-repair function. Numerous experiments had to be performed to answer questions such as:

  • Which type of cells from which A-T patients should be used?
  • How many cells should each drug be tested on (keeping in mind that there should ideally be only one layer of cells to make it easier to see what has happened)?
  • How much of the DNA-damaging chemical should be placed on the cells, and how long should the cells be exposed to it before the effects are measured?
  • Which protein is found to be produced sufficiently differently in A-T cells and could be measured to determine if a drug has helped restore the repair function in the A-T cells?
  • How much improvement must be seen in the cells to be considered significant and likely to help patients?
  • Will the test remain reliable and consistent when it is moved into an industrialized setting that uses robotics, automation and imaging technologies on a large-scale?

With these questions answered, the team will now run a pilot screen using the same methods and technologies that will be used later for the full screen. And then, if all goes as planned, they will screen over five thousand drugs in the third phase. Besides identifying “hits” (drugs that appear to help A-T cells), running this screen may generate new insights about the biology of A-T.

We’re encouraged by this progress, and we hope to be able to give you another update soon. Thank you to all of our donors and volunteers who have helped to make this happen!

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