Targeted Genome
Editor Delivery
Challenge

The discovery of CRISPR genome editing technology has greatly enhanced the potential to treat diseases. However, delivering genome editing components safely and effectively has proven to be challenging. The current lack of specific programmability is a key limiting factor for successfully scaling this technology. A variety of delivery approaches, including but not limited to those below, could potentially meet the need to target tissues and/or cells to advance these technologies into the clinic. To date, lipid nanoparticles (LNPs) are the most well studied non-viral targeted delivery systems. They are specialized for encapsulating nucleic acids and can be altered with ligands to improve delivery specificity. Compared to other synthetic polymer nanoparticles, LNPs have better biocompatibility and lower levels of toxicity. Currently, the liver is the most efficiently targeted organ for LNP based therapeutics. However, due to low delivery efficiency to primary cells and in in vivo animal experiments, the editing efficiency of LNPs is yet to meet clinical requirements in extra-hepatic tissues. After LNPs, polymer-based nanoparticles (PNPs) are the most used delivery vehicles. PNPs offer several benefits over LNPs since they are easier to manufacture, can be varied easily, and have improved circulation time. Inorganic nanoparticles are also gaining popularity as a vehicle for CRISPR based machinery due to their ability to be modified and their efficacy as a carrier for nucleic acids and small molecules. Other bio-inspired delivery vehicles such as exosomes, liposomal drug delivery systems, antibody/protein carriers, virus-like particles such as bacteriophages and nanobots have shown potential but have remained largely underutilized in the genome editor delivery field.

Solution Requirements

Solutions must be a highly efficient and programmable delivery system to deliver genome editing machinery that can target specific tissues (cells, types, and/or organs). Solutions must be able to be programmed to deliver to at least three distinct and different cell(s), tissue types, and/or organs and with delivery and editing capability that is at least as efficient as the current state of the art. An optimal solution would be straightforward to manufacture, low-cost, scalable and have a reasonable safety profile. Solutions that propose viruses and viral-like systems or particles must build on the field and meet the criteria demonstrating full understanding of how the delivery system can be modified so that it is programmable and can target a variety of different tissue targets (cells, types, and/or organs). The solution will be judged on how well it meets the criteria.

Programmable solutions that only target central nervous system (CNS) targets should be submitted under Target Area 2. Solutions that meet the requirements for Target Area 2 but also are programmable to target a non-brain organ may be submitted for consideration in both Target Areas, though solutions submitted to both Target Areas are only eligible for one prize.

To be highly competitive in this Challenge, Solutions must:

Solutions should also have these desired traits:

Additionally, solutions could:

The blood–brain barrier (BBB) is comprised of endothelial cells in the brain vasculature, as well as specialized glial cells (astrocytes) which surround blood vessels in the brain. The BBB prevents unwanted substances from entering into the extracellular fluid of the central nervous system. Given the vital importance of brain function, it is imperative that the influx and efflux of biological substances be carefully controlled for the appropriate functioning of the central nervous system. One practical consequence of the BBB is that it also blocks the uptake of many pharmaceuticals, including proteins and nucleic acids. This hinders development of treatments for brain related diseases. As such, an effective technology to deliver genome editing machinery across the blood-brain barrier to a substantial proportion of clinically relevant brain cell types would have broad implications for the treatment of many neurogenetic diseases.

To be highly competitive in this Challenge, Solutions must:

Solutions should also have these desired traits: