A large analysis of thousands of FDA-approved drugs carried out at the Max Planck Institute for Evolutionary Anthropology in Leipzig shows that a number of commonly used drugs can influence the efficacy of CRISPR-based gene editing therapies.
In addition, the researchers showed two proteins, estrogen receptor 2 (ESR2) and aldehyde oxidase 1 (AOX1) play an important role in the DNA repair pathway and identified some drugs that could potentially be repurposed as cancer therapies for specific DNA repair defects seen in some cancers.
“Every cell in the human body faces the threat of naturally occurring DNA double strand breaks. Double strand break repair pathways are therefore essential for preventing cell death,” explain lead author Stephan Riesenberg, PhD, a group leader at the Max Planck Institute for Evolutionary Anthropology, and colleagues in Nature Communications.
“Repair pathway choice is of great importance in genome editing and synthetic lethality. Consequently, clinically safe drugs that can alter repair pathway choice would be of great benefit for gene therapy and oncology.”
In the current study, the researchers carried out a lab-based CRISPR editing assay to model an environment where gene editing had occurred and study the potential effects of 2,344 FDA-approved drugs in more than 7,000 different conditions (e.g. different dosing) on this process.
“Understanding how everyday medicines interact with CRISPR-based treatments will be increasingly important as these therapies enter real-world clinical use,” said first author Dominik Macak, also based at the Max Planck Institute for Evolutionary Anthropology, in a press statement.
They found that a number of commonly used drugs did impact CRISPR gene editing. For example, tolterodine and orphenadrine, anticholinergic drugs prescribed for overactive bladder and as a muscle relaxant, respectively, raised the fraction of precise edits between 1.4-1.7 fold. In contrast, the cardiac glycoside ouabain, used to treat low blood pressure and heart rhythm disorders, distorted gene editing and was also toxic to edited cells.
The researchers also discovered the role of ESR2 and AOX1 in the DNA repair pathway, as well as finding new candidates for inducing synthetic lethality in cancer cells. Use of synthetic lethality as a therapy is based on the idea that two separate genetic weaknesses are tolerated on their own, but lethal together. If a cell already has a fault in one DNA repair pathway, blocking a second, compensating pathway with a drug pushes it over the edge and the cell dies. This is useful for targeting cancer cells with cancer specific mutations.
Riesenberg and team identified several drugs with potential to treat cancers with DNA repair mutations. For example, the antimalarial drug artemether and raloxifene, primarily used to treat osteoporosis, were good candidates for this, as was ouabain, as it caused profound cell death in cells with particular mutations linked to DNA repair.
“Our study identifies several approved medicines as promising candidates for treating cancers with DNA-repair deficiencies, offering potential options beyond current therapies,” said Riesenberg. “Nevertheless, additional research is needed to validate if our findings obtained from experiments with cultured cells would actually translate to real-world medical use.”
