TitanCas12i

TitanCas12i is a proprietary, engineered Type V-I CRISPR-Cas12i nuclease developed by Reforgene Medicine for in vivo therapeutic genome editing. Discovered through metagenomic mining using protein language models (PLM) and optimized via AI-driven protein engineering and AlphaFold structural modeling, TitanCas12i (specifically the Mut-10 variant) is a compact protein of approximately 1139 amino acids. It utilizes a 22-nucleotide hairpin-shaped CRISPR RNA (crRNA) and recognizes a WTN protospacer adjacent motif (PAM). Preclinical studies demonstrate that TitanCas12i achieves a 206% increase in editing activity compared to wild-type Cas12i and generates a broad deletion window. The system is typically delivered via lipid nanoparticles (LNPs) encapsulating codon-optimized mRNA and guide RNA (gRNA). It has been validated in preclinical models targeting key metabolic regulators, including ANGPTL3, AGT, LPA, and LDLR, for the potential treatment of cardiovascular and metabolic diseases.