Rapid Inhibitor Discovery and Development pipeLine (RIDDL)

Background
The Defense Advanced Research Projects Agency (DARPA) is seeking innovative proposals for the Rapid Inhibitor Discovery and Development pipeLine (RIDDL) program. The goal is to develop and demonstrate rapid methods for identifying and optimizing novel molecules that inhibit gene editing technologies, particularly CRISPR-Cas systems. This initiative aims to address the potential misuse of gene editing technologies by enabling quick responses through the discovery of effective inhibitors. The program emphasizes transformative approaches that enhance activity, specificity, utility, and potency of these inhibitors.

Work Details
The RIDDL program requires the development of a rapid discovery platform for inhibitors targeting novel gene editing systems, including Cas9 and Cas12. Key tasks include:
1. Establishing a discovery pipeline for inhibitors of emerging gene editors.
2. Developing in vitro models and assays to test candidate molecules.
3. Utilizing various mechanisms of action for novel inhibitors such as inhibiting DNA binding, cutting activity, or conformational changes necessary for nuclease activity.
4. Proposals must detail in vitro assays including robustness, sensitivity, dynamic range, and toxicity testing.
5. Plans for scaling up high-performing candidates for further development are essential.
6. Excluded approaches include engineering Cas variants with modulated activity, animal or human subject research, solely in silico methods without wet lab validation.

Period of Performance
The contract will be executed over a 30-month period divided into three phases: Phase I (10 months), Phase II (10 months), and Phase III (10 months). Each phase has specific milestones that must be achieved to progress to the next phase.

Place of Performance
The geographic location(s) for performance are not explicitly stated but may involve collaboration with various research institutions and laboratories.