Intellia Therapeutics’ Preclinical Data Show Continued Progress in In Vivo Gene Editing With Systemic Lipid Nanoparticle Delivery of CRISPR/Cas9 components
In several in vitro and in vivo preclinical studies, the data demonstrated:
- Editing efficiency in mouse liver of up to approximately 60 percent at the transthyretin (TTR) target site after a single intravenous administration, consistently across different lobes. This resulted in an associated decrease in serum TTR protein levels of up to approximately 80 percent;
- Dose-dependent editing by LNP delivery;
- Undetectable Cas9 mRNA and guide RNA (gRNA) in the liver at 72 hours post administration;
- Repair patterns in mouse liver cells in vivo being best predicted by primary mouse liver cells in vitro.
“Intellia has shown robust data that demonstrates the clinical potential of the LNP delivery of CRISPR components. With a single administration, we show significant editing at the target gene and a related decrease in target protein in serum,” said
The preclinical editing studies were designed to explore the use of lipid nanoparticles for delivery of CRISPR/Cas9 components to the liver in mice and to mediate editing of target DNA within hepatocytes. In general, for the LNPs in the studies, Cas9 mRNA was co-formulated with chemically synthesized gRNAs targeting the mouse TTR gene, and administered via one or two intravenous tail vein injections. Additional studies were performed to evaluate the impact on editing of variables including guide format, dosing regimen and dose escalation.
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward looking statements include, but are not limited to, statements regarding our ability to advance CRISPR/Cas9 into therapeutic products for severe and life-threatening diseases; the potential timing and advancement of our clinical trials; the impact of our collaborations with
ROBUST IN VIVO GENE EDITING IN MOUSE HEPATOCYTES WITH SYSTEMIC LIPID NANOPARTICLE DELIVERY OF CRISPR/CAS9 COMPONENTS
Jonathan D Finn,
There is considerable interest in the therapeutic potential of CRISPR/Cas9-mediated gene editing to treat a wide variety of genetic diseases; however, clinically viable delivery of CRISPR/Cas9 components presents an obvious challenge. Effective and safe delivery of CRISPR/Cas9 components, whether based on viral or non-viral delivery vehicles, would require specific targeting of a tissue or cell type; and brief half-life in order to minimize potential off-target activity and innate and humoral immune responses. In addition, the ability to re-administer the therapy to attain stable, therapeutically relevant levels of gene editing would be an advantage. With these requirements in mind, we have explored the use of lipid nanoparticles (LNPs) for delivery of CRISPR/Cas9 components to the liver to mediate editing of target DNA within hepatocytes. Cas9 mRNA and chemically synthesized gRNA specific to the mouse transthyretin gene (TTR) were co-formulated into LNPs, and administered to mice via intravenous tail vein injection. Various parameters were explored, including the nature of the guide RNA (sgRNA vs. dgRNA & chemical modification), the dosing regimen, and molecular strategy (single target site vs. two-target site micro-deletion). We found that the best results were obtained with a chemically modified single guide co-formulated with Cas9 mRNA. We were able to achieve a median dose-dependent editing of up to 55% of the gene copies in liver biopsies. A corresponding dose-dependent reduction of serum transthyretin protein levels was seen, with a decrease of up to 80%. The levels of editing across liver lobes were in general highly consistent. Notably, the DNA repair patterns in liver were distinctly different from those seen in cell lines using the same TTR-specific gRNA. These results demonstrate that therapeutically meaningful levels of in vivo CRISPR/Cas9-mediated gene editing can be obtained with a completely synthetic and scalable single-agent system, and suggest that the treatment of liver-based genetic disease with CRISPR/Cas9 will be clinically viable.
Jennifer Mound SmoterChief External Affairs & Communications Officer +1 224-804-4462 email@example.com Investor Contacts: John Graziano Trout Group+1 646-378-2942 firstname.lastname@example.org Chad Rubin Trout Group+1 646-378-2947 email@example.com