Naturegenic’s pipeline focuses on addressing Smith-Lemli-Opitz syndrome, a condition stemming from the hereditary inactivation of 7-dehydrocholesterol reductase, a protein responsible for the final step in cholesterol biosynthesis. With over 160 documented mutations across 8 exons of this gene, attempting to correct each mutation using CRISPR prime editors or base editors is not a practical approach. Instead, our strategy involves introducing a new functional gene copy into the gene locus to replace the defective gene.
Named CRISPR SEL ONLI, which stands for CRISPR Sticky Ends Ligation for ONe Locus Integration, our method leverages the unique attributes of the Cas12a genome editing system. This enables precise cutting of the gene locus followed by replacement with a functional gene copy. Our approach encompasses two treatment versions: mRNA treatment and engineered hematopoietic stem cell (HSC) treatment.
The first approach involves using lipid nanoparticle (LNP) encapsulated mRNA, which is administered intravenously. This mRNA eventually reaches liver cells where it replaces the faulty enzyme variant, initiating the conversion of toxic 7-dehydrocholesterol into cholesterol. In the second approach, we engineer the patient’s own hematopoietic stem cells (HSCs) using the CRISPR SEL ONLI technology. These modified HSCs are then amplified and reintroduced into the patient. As the engineered HSCs generate functional blood cells, they reach brain tissues that accumulate excessive 7-DHC levels, catalyzing the conversion to cholesterol.
Our initial focus is on manufacturing the first mRNA drug under Good Manufacturing Practices (GMP) and launching preclinical studies. Simultaneously, for the engineered HSC treatment, we are enhancing the efficiency of gene replacement. Once we achieve a replacement efficiency of up to 60% within a year, we will initiate pre-clinical studies for this second treatment approach.