On October 20, 2021 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported new data supporting novel capabilities of its CRISPR/Cas9 genome editing platform, which the Company plans to leverage for the development of future therapeutic candidates (Press release, Intellia Therapeutics, OCT 20, 2021, View Source [SID1234591588]). The data shared showed that Intellia’s allogeneic platform, leveraging a novel combination of sequential gene edits, can prevent immune rejection of allogeneic T cells in in vitro and in vivo models for future application in TCR-T and CAR-T therapy. Additionally, data highlighted that lipid nanoparticles (LNPs) can replace electroporation for delivery of CRISPR/Cas9 gene edits to T cells, avoiding the risk of chromosomal translocations observed when multiple edits are performed simultaneously, as well as the negative effect of electroporation on T cell health. Finally, results from an ongoing study demonstrated proof-of-concept in non-human primates (NHPs) for in vivo gene insertion and knockout for the treatment of alpha-1 antitrypsin deficiency (AATD), which resulted in sustained production of normal human levels of healthy alpha-1 antitrypsin (A1AT) protein and reduction of the endogenous disease-associated protein. The data were presented at the 29th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT) meeting, taking place virtually from October 19 – 22, 2021.
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"Preclinical data presented at ESGCT’s Annual Congress show that using our proprietary genome editing platform, Intellia is able to accomplish multiple CRISPR/Cas9 edits in both in vivo and ex vivo applications, advancing our efforts to develop treatments for challenging genetic diseases like alpha-1 antitrypsin deficiency and to potentially expand both the effectiveness and availability of engineered cell therapies for the treatment of cancer and autoimmune diseases," said Intellia President and Chief Executive Officer John Leonard, M.D. "This important preclinical work supports our mission as we look ahead to initiating a first-in-human study of NTLA-5001, our first ex vivo candidate, in patients with acute myeloid leukemia, and nominating at least one new development candidate before the end of this year as well as additional candidates in 2022."
Proprietary allogeneic solution that can be readily deployed for TCR-T and CAR-T therapy
Key immunological challenges remain unaddressed by allogeneic, or "off-the-shelf", T cell therapies currently in development for cancer treatment. Leveraging Intellia’s CRISPR/Cas9 platform and an innovative sequential gene editing process, the Company has developed a proprietary allogeneic solution that may avoid the need for long-term or aggressive immunosuppressive regimens and could be readily deployed for TCR-T and CAR-T therapy. The data shared at ESGCT demonstrate that a novel combination of targeted gene edits protected therapeutic T cells from host T cell as well as NK cell-mediated killing in in vitro and in vivo mouse models. Furthermore, these engineered cells showed no impairment in their tumor-killing ability in in vitro assays compared to their autologous counterparts. As part of these efforts, Intellia intends to nominate its first allogeneic cell therapy development candidate by the first half of 2022.
Using lipid nanoparticles to engineer next-generation CRISPR-based cell therapies
Adoptive cell therapies have been successful in certain cancers but have encountered technical and biological barriers, such as reliance on electroporation for editing of T cells, which impacts T cell viability, expansion and gene expression, and can lead to chromosomal translocations when used to introduce multiple simultaneous gene edits. At ESGCT, Intellia presented data demonstrating the use of LNPs to engineer CRISPR-based T cell therapies without the need for electroporation, advancing a robust, modular and scalable platform with the potential to enable future allogeneic and solid tumor therapies requiring multiple genome edits. The data showed that T cells engineered with LNPs showed efficient editing rates, with improved cell properties and performance both in vitro and in vivo, as compared to electroporation. In addition, the lower toxicity associated with LNP delivery allows Intellia’s platform to produce sequentially edited T cells with high efficiency, faster expansion and minimal translocations as compared to electroporation – demonstrated by targeting up to five or more loci (four knockouts and one to two targeted, in-locus insertions). The data support the ability of this platform to be used for a variety of targeting modalities, including CARs and TCRs, to support both autologous or allogeneic T cell candidates, including those requiring multiple edits to address immune rejection and activity in solid or other immune-suppressive tumors. This LNP-based approach is already being used for NTLA-5001, the Company’s first wholly owned ex vivo genome editing candidate, which is in development for acute myeloid leukemia. Intellia expects to initiate patient screening for the Phase 1/2a study of NTLA-5001 by year-end.
Tailored genome editing approach offers potential to independently treat liver and lung manifestations of alpha-1 antitrypsin deficiency (AATD)
New data shared at ESGCT represent the first reported demonstration of consecutive in vivo gene insertion and gene knockout in NHPs. This is an important step toward treating diseases such as AATD, which can manifest as lung disease (due to insufficient functional A1AT protein levels) or liver disease (due to accumulation of mutant A1AT protein) and thus require either inserting a functional gene, removing a disease-associated gene or both. The Company reported data showing that insertion of a healthy form of the SERPINA1 gene, which encodes the A1AT protein, led to normal human A1AT levels in NHPs which were durable through 52 weeks in an ongoing study. Intellia has also now tested the ability to knock out the endogenous cynomolgus SERPINA1 gene while leaving the inserted healthy human version intact. This insertion followed by knockout led to the continued production of normal human levels of functioning A1AT protein — substantially higher than what has been seen with other treatment approaches — as well as reduction of the disease-associated protein. Together, these data support the ability of Intellia’s in vivo genome editing platform to address the lung and/or liver manifestations of AATD as needed for a given patient.
Presentations will be available on Intellia’s website at www.intelliatx.com.