Patient-Driven Discovery

Traditional drug discovery typically involves the following steps

  1. determining a molecular target believed to be related to a disease,
  2. developing an assay to detect either inhibition or activation of that target,
  3. screening large libraries of compounds searching for a modulator of that target,
  4. verifying that the compounds discovered in #3 have activity in cells.
  5. verifying that the compounds have activity in an animal model of the disease
  6. verifying that the compound is safe
  7. making modifications to the structure of the lead compound to increase its efficacy and improve its safety.
  8. After the compound is optimized, it is nominated for testing in patients.

It is a long and laborious process and frequently compounds that work in the screen don’t work in cellular models, or compounds that work in cellular models don’t work in animal models.  Furthermore, animal models of many diseases take a long time to run (weeks), require lots of compound, are variable, and most of all are poorly predictive of human disease.  And so, after all this experimentation, and all these animal models, many compounds don’t work when they’re tried in humans for the first time in clinical trials.

At Sharp Edge Labs we’re doing something different.  Because we work in monogenic diseases, and because Stem-Cells from patients with the specific gene-defect are available, we can effectively bring patients into the earliest stages of drug discovery.  Our Discovery process looks like this.

  1. Develop a cellular assay to detect trafficking for a protein known to be defective in a monogenic disease.
  2. Screen compound libraries for their effect on cellular trafficking of the mutated target (looking for correctors)
  3. Test corrector compounds in patient-derived cells to verify that the target is also corrected in patient cells.
  4. Determine that the compound is safe.
  5. After the compound is optimized, it is nominated for testing in patients.

By contrast to the traditional approach, patients don’t recieve the compound for the very first time in a clinical trial, but rather their cells are used to determine promising compounds directly out of the trafficking screen, and activity in patient cells guides the optimization of the compound throughout the preclinical discovery process.  Note also there are no animal models used to nominate a compound for clinical trials.  For mongenic diseases no animal model is better than showing a corrective effect on the defective protein in cells from patients with the disease.  Another contrast; by the time the first compound is being administered to patients in the clinic, there will be a long history of activity in patient cells (in fact, some of those cells may come from the very patients who enroll in the trial).

We think this new patient-driven discovery paradigm is going to have a profound effect on our ability to bring truly effective therapies to patients sooner, more safely, and more precisely than was previously possible.