On October 18, 2018 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported its new data from three of its programs, including the company’s first data on complex edits, at the 26th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT), in Lausanne, Switzerland (Press release, Intellia Therapeutics, OCT 18, 2018, View Source [SID1234530291]).
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"We are extremely pleased to present an outstanding compilation of data today reflecting progress in our preclinical genome editing programs," said Intellia President and Chief Executive Officer John Leonard, M.D. "We showed that we can efficiently introduce complex edits in mice by inserting genes to express proteins that are deficient in some genetic diseases. By using our LNP delivery system in combination with AAV to deliver template DNA, we are opening the door for the development of therapies for a wide range of genetic diseases that require stable gene insertion and expression. In parallel, we are driving forward our ex vivo programs and other in vivo programs. Our researchers are gaining further insights into our ATTR program through our ongoing NHP studies, as well as working with our collaborators at Ospedale San Raffaele (OSR) to make excellent progress in our quest to advance the next generation of engineered cell therapy."
CRISPR-mediated, Targeted Gene Insertion Data
In a collaboration between Intellia and Regeneron Pharmaceuticals, Inc., researchers combined Intellia’s modular lipid nanoparticle (LNP) delivery system of CRISPR/Cas9 with a modular adeno-associated viral (AAV) insertion template to achieve supratherapeutic levels (levels higher than those required in a clinical setting) of gene expression in mice. Using Factor 9 (F9) as a model gene, the team demonstrated the first robust, efficient CRISPR-mediated targeted insertion into the liver. F9 is a gene that encodes Factor IX (FIX), a blood-clotting protein that is often missing or defective in hemophilia B patients.
Using Intellia’s proprietary bi-directional template, researchers detected hybrid mAlb-hF9 transcripts in >50 percent of hepatocytes following a single dose. Circulating human FIX protein levels of >30,000 ng/mL were achieved, which are predicted to correspond to levels 40-300 times higher than those capable of preventing bleeding episodes in hemophilia B patients, when using a wildtype or hyperfunctional version of F9 (sources: George, et al, NEJM, 2017; Simioni et al, NEJM, 2009). Researchers were able to vary FIX levels by modulating either the LNP or the AAV dose, and expression levels remained stable and ongoing in all cases throughout 12 weeks of observation.
This approach was repeated with Intellia’s wholly owned preclinical in vivo program in alpha-1 antitrypsin deficiency (AATD), another genetic disease of the liver associated with a mutation in the SERPINA1 gene that causes liver and lung dysfunction. Researchers used the LNP-AAV delivery combination of CRISPR/Cas9 components to insert donor template DNA encoding the SERPINA1 gene for AATD. The insertion resulted in blood protein levels in mice that corresponded to a range of SERPINA1 systemic levels required for normal lung function in humans.
Today’s presentation, titled "Supra-therapeutic levels of transgene expression achieved in vivo by CRISPR/Cas9 mediated targeted gene insertion," was made by Jonathan Finn, Ph.D., executive director, platform biology, Intellia. This presentation will be accessible through the Events and Presentations page of the Investor Relations section of Intellia’s website at www.intelliatx.com.
New Non-Human Primate Data from Intellia’s ATTR Program
Intellia also presented new data from non-human primate (NHP) studies in its transthyretin amyloidosis (ATTR) program further demonstrating a high correlation between liver editing and reduction of the transthyretin (TTR) protein. ATTR is a systemic, debilitating and fatal disease caused by one of approximately 136 different inherited mutations in the TTR gene. The company found that a liver editing rate of only ~35-40 percent in NHPs is needed to achieve a therapeutically meaningful reduction of TTR, specifically a TTR protein reduction of >60 percent. The data also demonstrated the transient nature of Intellia’s proprietary modular LNP delivery system, which was rapidly cleared from circulation, with all CRISPR/Cas9 components undetectable within five days of administration. Furthermore, rates of editing were durable over a six-month period without re-dosing the animals.
These data included results from ongoing collaborations with researchers at Regeneron and the University of Porto in Portugal, where ATTR is endemic in certain populations. Today’s presentation, titled "Delivering on the therapeutic potential of CRISPR/Cas9: Development of an LNP-mediated genome editing therapeutic for the treatment of ATTR," was made by Yong Chang, Ph.D., vice president, safety pharmacology, Intellia. This presentation will be accessible through the Events and Presentations page of the Investor Relations section of Intellia’s website at www.intelliatx.com.
Data Update from Intellia’s Acute Myeloid Leukemia Program
In a presentation titled "Hunting novel WT1-specific T cell receptors for immune gene therapy of acute myeloid leukemia," Intellia and its research collaborator, OSR, led by Chiara Bonini, M.D., Ph.D., deputy director of the Division of Immunology, Transplantation and Infectious Diseases at San Raffaele Hospital and University, shared an update on the company’s lead ex vivo program in acute myeloid leukemia (AML). Researchers presented in vitro data showing that CRISPR/Cas9 editing resulted in over 90 percent knockout of endogenous T cell receptors (TCRs). Subsequent transduction of Wilms’ Tumor 1 (WT1)-specific transgenic TCRs led to high expression of the inserted TCR with over 95 percent purity in isolated cytotoxic T cells (CD8+ T cells). T cells were fully functional and specifically killed leukemic blast cells that expressed the WT1 antigen and HLA-A*02:01 allele. Several additional TCRs directed to multiple WT1 epitopes and human leukocyte antigen (HLA) alleles are under investigation, including undergoing in vitro and in vivo functional testing.
Intellia and OSR are collaborating to develop best-in-class CRISPR-edited T cells directed to a specific epitope of WT1, a tumor-associated antigen overexpressed across a wide range of different tumor types and a known driver of leukocyte blasts in hematological cancers. Intellia’s first cell therapy tumor target is WT1 for the treatment of AML and other potential hematological malignancies, as well as for solid tumors.