On October 24, 2019 Intellia Therapeutics, Inc. (NASDAQ: NTLA), a leading genome editing company focused on the development of curative therapeutics using CRISPR/Cas9 technology is reported one oral presentation and four poster presentations at the 27th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) meeting taking place October 22-25, 2019, in Barcelona, Spain (Press release, Intellia Therapeutics, OCT 24, 2019, View Source [SID1234542481]).
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"We are excited to share progress across Intellia’s in vivo and ex vivo programs at this important scientific venue," said Laura Sepp-Lorenzino, Ph.D., chief scientific officer, Intellia Therapeutics. "Our data shows the complexity of the edits we are able to make with CRISPR/Cas9, while achieving important therapeutically relevant results. We are building on the success of our modular platform now having demonstrated consecutive targeted knockout and insertion genome edits in preclinical studies. Additionally, we presented data from our engineered cell therapy program, which continues to demonstrate the use of CRISPR/Cas9 for combined knockout and targeted integration in human T cells."
Intellia Demonstrates Consecutive In Vivo Genome Editing in Alpha-1 Antitrypsin Deficiency Mouse Model
Intellia’s oral presentation highlights its alpha-1 antitrypsin deficiency (AATD) study showing that consecutive dosing of two distinct lipid nanoparticle (LNP) formulations, in adult mice, achieves two targeted genome editing events, resulting in knocking out the faulty gene and restoring therapeutic levels of normal alpha-1 antitrypsin protein (hAAT). Intellia’s approach for AATD uses a modular hybrid delivery system combining a non-viral LNP which encapsulates CRISPR/Cas9 with an adeno-associated virus (AAV) carrying donor DNA template. Compared to traditional viral-based delivery of gene editing components, Intellia’s LNP delivery system can overcome the inherent limitations of immunogenicity to facilitate multiple in vivo gene editing events.
In a mouse model harboring the human PiZ allele, the most severe genetic defect in AATD patients, Intellia first reduced expression of the defective protein using gene knockout. Three weeks following the PiZ allele knockout, Intellia inserted the normal human alpha-1 antitrypsin gene, resulting in stable (throughout 12 weeks of observation), therapeutically relevant circulating protein levels. In the study, a sustained reduction of the circulating PiZ protein levels of >98% was observed for over 15 weeks. This is the first in vivo demonstration of a non-viral delivery platform, enabling a consecutive dosing approach for achieving multiple genome edits in the same tissue of the same animal. Intellia’s oral presentation, titled "In Vivo Gene Knockout Followed by Targeted Gene Insertion Results in Simultaneous Reduced Mutant Protein Levels and Durable Transgene Expression," will be given by Anthony Forget, Ph.D., on October 25, 2019. This presentation will be available on Intellia’s website at www.intelliatx.com.
Intellia’s Poster Presentations
WT1-Specific TCR Engineered Cell Therapy Studies
Intellia presented new in vitro data showing that CRISPR/Cas9-mediated genome editing for in locus insertion, combined with endogenous T Cell Receptor (TCR) knockout, leads to significant reduction in mispairing of endogenous and transferred TCR chains. This approach is expected to generate transgenic-TCR (tg-TCR) T cell therapies for hematological cancers and solid tumors. Results demonstrate a highly efficient reduction of >98% in endogenous TCR α and β chains while reaching >70% insertion rates of tg-TCRs without further purification. The poster titled "Engineering of Highly Functional and Specific Transgenic T Cell Receptor (TCR) T Cells Using CRISPR-Mediated In Locus Insertion Combined with Endogenous TCR Knockout," was presented on October 24, 2019, by Birgit Schultes, Ph.D.
Researchers also presented in vitro data showing that a library of WT1-specific TCRs were generated, several of which Intellia is currently evaluating as part of its lead engineered cell therapy program targeting Acute Myeloid Leukemia (AML). This presentation, "Generation of a Library of WT1-Specific T Cell Receptors (TCR) for TCR Gene Edited T Cell Therapy of Acute Leukemia," was presented on October 23, 2019 by Intellia’s collaborator, Erica Carnevale, Ph.D., IRCCS Ospedale San Raffaele.
Primary Hyperoxaluria Study
Intellia showed the continued progression of its modular platform capability using CRISPR/Cas9 to knockout either hydroxyacid oxidase 1 (Hao1) or lactate dehydrogenase A (Ldha), leading to a dose-dependent and persistent reduction of urinary oxalate levels in a Primary Hyperoxaluria Type 1 (PH1) mouse model. Data shows Ldha gene disruption also decreased LDH enzyme activity in the liver and did not impair the disposition of lactate in either wild type or renally-impaired mice. These results highlight the potential of editing genes in the glyoxylate detoxification pathway using a non-viral delivery approach as a one-time treatment option for PH1. These data were presented as a poster, titled "CRISPR/Cas9-Mediated Gene Knockout to Address Primary Hyperoxaluria," by Sean Burns, M.D., on October 24, 2019.
Off-Target Screening Platform
Intellia demonstrated its approach to assess off-target activity to identify highly specific CRISPR/Cas9 guides. Results from targeted off-target sequencing in edited cells showed that biochemical off-target discovery approaches were the most sensitive and accurate. These data were presented as a poster on October 23, 2019, titled "In Silico, Biochemical and Cell-Based Integrative Genomics Identifies Precise CRISPR/Cas9 Targets for Human Therapeutics," by Dan O’Connell, Ph.D.