Getting into the liver with CRISPR

Data from Intellia show continued progress in in-vivo gene editing with systemic lipid nanoparticle delivery

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CAMBRIDGE, Mass.—One of the big challenges with things like RNAi treatments—and more recently, with gene editing—is getting the therapeutic where it needs to go, as well as getting it to deliver the actual changes at the genetic level. Well, in mid-August, Intellia Therapeutics Inc., a leading genome-editing company focused on the development of potentially curative therapeutics using CRISPR/Cas9 technology, presented preclinical data demonstrating in-vivo gene editing using lipid nanoparticles (LNPs) to deliver CRISPR/Cas9.
These data were presented at the 2016 meeting on Genome Engineering: The CRISPR/Cas Revolution, in Cold Spring Harbor, N.Y. 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.
The company says that 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.
By way of explaining the rationale for the LNP delivery strategy, the study researchers noted in their abstract, “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.”
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.
“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 Dr. David Morrissey, chief technology officer of Intellia Therapeutics. “These early data also show that LNP delivery can lead to rapid clearance of the Cas9 and guide components from the liver, an important consideration for future clinical studies. Intellia continues to make further advances, and we would expect greater editing efficiency with continued optimization.”
Leerink Partners analysts were upbeat on the news, noting that the company’s data continue to
demonstrate the rationale and potential of the LNP platform “to efficiently deliver the gene-editing payload to the liver ... We have a positive view of [Intellia’s] risk-diversified pipeline strategy and partnerships with [Novartis] and [Regeneron] that serve as strong validation for the platform and IP position. While the pending CRISPR patent interference case could continue to dominate the headlines in the press near term, ultimately a settlement could be the most likely outcome of the dispute, which we think could take several years to resolve.”
Leerink recently upgraded the company’s stock to Outperform and continues to believe that Intellia “is well positioned among CRISPR companies to capitalize on the promise of gene-editing technology long term.”
“Whereas other genome-editing technologies are being developed, it’s the simplicity, scalability and ability to optimize at speed that sets CRISPR apart,” the Leerink analysts wrote, noting that Intellia’s scientific founders and advisors include pioneers in CRISPR/Cas9 biology, nucleic acid delivery and clinical translation. “While clinical proof of concept for the technology is still outstanding, [Intellia] has developed a risk-diversified ‘sentinel’ pipeline strategy aimed at employing different editing strategies to explore the scope of the CRISPR/Cas9 system and generate proof of concept of the various facets of the technology, including delivery, type of edit and selectivity and efficiency.”

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