Selective Cell Elimination using RNA-guided Chromatin Shredding

Patent Status

Patent Pending

Brief Description

Cancer is driven by genetic mutations, notably in TP53, which is altered in ~50% of all cancer cases across various types. In certain cancers such as ovarian, non-small cell lung (NSCLC), and pancreatic cancers, up to 70–90% of cases are found to have TP53 mutations. TP53 mutations also tend to be clonal, arising early and persisting across tumor cells in a heterogenous population. Restoring p53 function for tumor regression has been considered the "holy grail" of cancer therapy. However, no approved therapies are available to target the p53 protein due to its lack of druggable pockets and the difficulty of re-activating defective transcription factors. Conventional treatments like chemotherapy induce systemic DNA damage, leading to widespread side effects.  Therefore, there is a need for compositions and methods that address the above.

UC Berkeley researchers and collaborators at Utah State University and the University of Utah have developed methods and compositions for cleaving chromosomal DNA in a eukaryotic cell that address some of the problems with cancer therapies mentioned above.  Such methods generally include contacting a target RNA inside of a eukaryotic cell with a CRISPR complex that includes a Cas12a2 protein and a guide RNA.  The Cas12a2 is programmed to selectively kill cancer cells by targeting cancer-specific transcripts. This approach eliminates cancer cells by inducing trans chromatin cleavage, triggering DNA damage and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations.

Suggested uses

• kill cancer cells by targeting cancer-specific transcripts
• kill latent HIV-infected T cells by targeting HIV transcripts
• kill HBV-infected cells by targeting HBV transcripts
• kill other virus-infected cells by targeting viral transcripts
• kill autoimmune T cells or other unwanted T cells by targeting transcripts of specific T cell receptors

Advantages

• RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations