The Incisive Delivery System™ (IDS) is a lipid nanoparticle-based platform which allows for the delivery of pre-formed active CRISPR complexes of Cas9 and guide RNA or ribonucleoprotein (RNP) into target cells. By delivering the active protein complex, we avoid problems that accompany the delivery of the nucleic acid instructions, as outlined below. The IDS platform offers significant advantages over other modes of CRISPR delivery, namely, nucleic acid or viral delivery techniques.
Our unique platform is based on the application-agnostic nature of all of the components of the final therapeutic. The IDS encapsulates CRISPR proteins (such as Cas9) that are already complexed to the targeting guide RNA. The guide RNAs have similar chemistry for any gene target, modified only in their sequence to allow for specific gene binding. Therefore, with this platform we can create a host of genome editing therapeutics, based on essentially the same material composition. The benefit of this platform is realized in the opportunity to establish the core components that will be used in every therapeutic going forward. With each approval, the IDS will shepherd the use of those components as standard solutions.
CRISPR is a powerful genome-engineering tool with two main components: the Cas endonuclease (enzyme that cuts DNA) protein, and the guide RNA that tells the protein where in the DNA to cut. By changing the nucleic acid sequence of the guide RNA, the Cas protein can be targeted to any gene, allowing for specific DNA manipulation. This powerful tool opens the possibility of changing the DNA of affected patients, opening the door for permanent cures of genetic diseases.
Currently CRISPR is delivered using viral delivery techniques or as individual nucleic acid templates, both approaches have significant limitations.
Failure of individually expressed components to bind and form active CRISPR complex.
Persistent expression of components such as Cas9 enzymes in cells.
The Incisive Delivery System™ (IDS) offers significant advantages over other modes of CRISPR delivery, namely, nucleic acid or viral delivery techniques.
The IDS delivers the CRISPR ribonucleoprotein (RNP) complex: the pre-assembled protein and guide RNA components, allowing quick on-target action of the cargo, followed by natural degradation and clearance of these components by existing cell mechanisms. Since the protein and guide RNA are already pre-complexed into the ribonucleoprotein (RNP), the two pieces do not need to find each other inside the cell, allowing for increased efficiency and efficacy, before being degraded and cleared after making the edit to the DNA.
This degradation is an important step in gene editing, as the RNP complex may be capable of off-target cutting of the DNA if it remains active for a long period of time. Delivery of the active RNP allows for quick action (cutting) and quick clearance of the components, decreasing the risk of off-target effects.
The IDS platform is compatible with any combination of endonucleases and guide RNAs. By changing the guide RNA sequence, it can be used to deliver cargo that targets almost anywhere in the human genome.
Delivers functional CRISPR components
Enables delivery of multiple genetic cargoes
Alleviates in cell production and failed connections
Unlike AAV, the body does not produce antibodies to LNPs
The Incisive Delivery System™ is compatible with any combination of endonucleases and guide RNAs. By changing the guide RNA sequence, it can be used to deliver cargo that targets almost anywhere in the human genome.
