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Abstract: SA-PO328

High-Throughput Discovery of Novel Therapeutic Candidates for Human Podocytopathies

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Barreto, Amanda, Duke University, Durham, North Carolina, United States
  • Burt, Morgan A., Duke University, Durham, North Carolina, United States
  • Samanta, Labannya, Duke University, Durham, North Carolina, United States
  • Musah, Samira, Duke University, Durham, North Carolina, United States

Group or Team Name

  • Musah Lab.
Background

Chronic kidney disease (CKD) impacts 12% of the world population. Currently, the best treatment options for patients experiencing advanced stages of CKD include dialysis or kidney transplantation. Therefore, there is an urgent need for novel therapies that address the underlying causes of kidney dysfunction and disease progression. Damage to podocytes is associated with CKD. In addition to comorbidities and predisposition factors, CKD occurrence can be aggravated by the administration of prescription drugs. These compounds include the chemotherapy drug Adriamycin (ADR), which exhibits off-target nephrotoxic effects in podocytes.

Methods

By employing our established protocol for hiPSC-derived podocytes, we developed a high-throughput screening (HTS) strategy to help discover new protective biomolecules and potential therapeutic candidates for podocytes. We screened the hiPSC-podocytes with a library of bioactive molecules and ADR. To eliminate the compounds that did not protect against ADR injury, the threshold for positive hits was considered above ADR control viability. These compounds were selected as potential hits and were subject to low-throughput secondary validation metrics.

Results

The cells co-treated with the bioactive hits and ADR seemed to have been protected from ADR-induced injury by retaining healthy cell spread, and cytoskeletal structures such as actin fibers. In subsequent 48hrs experiments, podocytes were pre-treated with the compounds in low-throughput environments, and podocyte cell viability and cytoskeleton arrangement were protected against ADR injury.

Conclusion

Our preliminary work led to the identification of three new compounds that protected human stem cell-derived podocytes from severe injury by ADR treatment in vitro. Ultimately, a podocyte-directed therapeutic could protect cells against known nephrotoxic drugs, potentially reducing the need for dialysis or kidney replacement in the future.

(A) Schematic of HTS and validations. (B) Fluorescent images of potential therapeutic hits compared to controls.

Funding

  • Other NIH Support