In Vivo Therapies

Our modular approach enables us to optimize the power and versatility of the CRISPR/Cas9Adapted from a naturally occurring bacterial immune system, CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats. One of the proteins in the CRISPR system is known as CRISPR-associated 9 protein or Cas9 protein, which acts as a pair of ‘molecular scissors’ to cleave DNA. Researchers have co-opted the bacterial CRISPR/Cas9 system to make specific changes in the DNA of humans, other animals and plants. CRISPR/Cas9 was first harnessed in 2012 as a genome editing tool in the lab. More recently, scientists have begun engineering and testing CRISPR systems to be very specific to a desired genetic target. technology and, importantly, allows us to rapidly develop therapeutics for numerous diseases that currently have limited treatment options.

Transthyretin (ATTR) AmyloidosisAlso known as ATTR amyloidosis. A rare genetic disease caused by accumulation of misfolded transthyretin (TTR) protein, which affects the nerves, heart, kidneys and eyes. Patients can develop amyloidosis by inheriting the faulty TTR gene from a parent (hereditary ATTR amyloidosis, ATTRv or hATTR) or due to a natural form of this protein, without genetic mutation (wild-type ATTR amyloidosis, ATTRwt or wtATTR). NTLA-2001, Intellia’s first investigational therapy, is being evaluated in a Phase 1 clinical trial as a treatment for people who have hereditary ATTR with polyneuropathy. Program:

• NTLA-2001 is an investigationalIn a research or clinical setting, investigational means that the drug has not been approved or authorized for use in patients outside of a clinical trial by any authority that regulates new treatments, such as the U.S. Food and Drug Administration (FDA) or United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). therapy for the treatment of ATTRAlso known as ATTR amyloidosis. A rare genetic disease caused by accumulation of misfolded transthyretin (TTR) protein, which affects the nerves, heart, kidneys and eyes. Patients can develop amyloidosis by inheriting the faulty TTR gene from a parent (hereditary ATTR amyloidosis, ATTRv or hATTR) or due to a natural form of this protein, without genetic mutation (wild-type ATTR amyloidosis, ATTRwt or wtATTR). NTLA-2001, Intellia’s first investigational therapy, is being evaluated in a Phase 1 clinical trial as a treatment for people who have hereditary ATTR with polyneuropathy. amyloidosis. It is the first CRISPR candidate to be administered systemically, or intravenously, to edit a gene inside the human body. By applying the company’s in vivoMeaning “within the living”, this type of therapy is administered directly into the patient, targeting the cells and editing the genome from inside the body. liver knockoutInactivation/deletion of a DNA sequence using a gene editing technology, such as the CRISPR/Cas9 system. This is the type of gene edit employed by NTLA-2001. approach, NTLA-2001 has the potential for lifelong reduction of TTR proteinAlso known as TTR protein. Produced by the TTR gene. The disease, transthyretin (ATTR) amyloidosis, occurs when a specific DNA mutation occurs in the TTR gene that causes the liver to produce the TTR protein in a misfolded form. This misfolded protein can build up in the body and lead to disease-causing nerve and other organ damage. and reversing disease progression with a single dose of treatment. The investigational therapy is delivered with Intellia’s proprietary non-viral lipid nanoparticleAlso known as LNP. LNPs are fat-based molecules that are the basis of Intellia’s CRISPR/Cas9 delivery platform. In Intellia’s experimental treatments, an LNP delivers to its target gene a simple, two-part genome editing system: the messenger RNA that encodes the Cas9 protein and the guide RNA that can target a specific DNA sequence. platform, which the company is using to develop other in vivo treatments. Our goal is to address all forms of ATTR amyloidosis, regardless of disease type, with a single dose of treatment.

• ATTR is a progressive and fatal disease that results from the build-up of a misfolded form of the TTR proteinAlso known as TTR protein. Produced by the TTR gene. The disease, transthyretin (ATTR) amyloidosis, occurs when a specific DNA mutation occurs in the TTR gene that causes the liver to produce the TTR protein in a misfolded form. This misfolded protein can build up in the body and lead to disease-causing nerve and other organ damage., leading to diverse disease manifestations and disease progression, including peripheral neuropathy and cardiomyopathyATTR amyloidosis resulting in heart muscle disease, and manifested through symptoms that include shortness of breath, palpitations and abnormal heart rhythm, ankle swelling (edema), fainting, fatigue and chest pain (angina). Can also lead to heart failure. Intellia is currently investigating NTLA-2001 as a treatment for people who have hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN or hATTR-PN). In the future, Intellia's goal is to address hereditary and wild-type ATTR amyloidosis, both polyneuropathy and cardiomyopathy, with a single dose of treatment..
• Intellia’s proprietary non-viral platform deploys lipid nanoparticles to deliver to the liver a two-part genomeA genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than three billion DNA base pairs—is contained in all cells that have a nucleus. editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 enzyme, which carries out the precision editing. Robust preclinical data, showing deep and long-lasting transthyretin (TTR) reduction following in vivo inactivation of the target gene, supports NTLA-2001’s potential as a single-administration therapeutic for ATTR. Interim Phase 1 clinical data presented in June 2021 and in June 2022, demonstrated substantial, dose-dependent reduction of TTR protein following a single dose of NTLA-2001.
• Intellia leads development and commercialization of NTLA-2001 as part of a multi-target discovery, development and commercialization collaboration with Regeneron.

Hereditary AngioedemaAlso known as HAE. Rare and potentially life-threatening genetic disease characterized by overproduction of bradykinin, which leads to recurring, severe and unpredictable swelling in various parts of the body. (HAE) Program:

• NTLA-2002 is Intellia’s wholly owned development candidate for the treatment of HAE and is our second in vivo knockout therapeutic candidate. NTLA-2002 is currently being studied in a first-in-human Phase 1/2 clinical trialA test of a new medical treatment or procedure in human volunteers with the purpose of evaluating a medical, surgical or behavioral intervention. Clinical trials typically follow preclinical (non-human) studies and are the primary way that clinical researchers and regulatory agencies evaluate whether a new treatment is safe and effective in people..
• HAE is a rare genetic disorder characterized by recurring and unpredictable severe swelling attacks in various parts of the body, and is significantly debilitating and disabling. The disease is caused by increased levels of bradykinin, a protein which leads to swelling. NTLA-2002 aims to prevent unregulated production of bradykinin by inactivating the kallikrein B1 (KLKB1Also known as KLKB1 gene. Knocking out this gene is expected to reduce kallikrein activity, which is involved in the biological pathway for release of bradykinin. Intellia expects this reduction to correlate with a decrease in bradykinin activity, thus, preventing the activation of endothelial cells that causes vascular leakage and angioedema in HAE patients.) gene, which encodes for prekallikrein, the kallikrein precursor protein, through a single dose of treatment to ameliorate the frequency and intensity of these swelling attacks.

Alpha-1 Antitrypsin DeficiencyAlso known as AATD. A genetic disorder with multiple manifestations, including lung dysfunction and progressive liver disease. Programs:

• NTLA-3001 is Intellia’s first and wholly owned CRISPR/Cas9-mediated in vivo targeted gene insertionInsertion of a new DNA sequence into the genome to manufacture a desired protein using a gene editing technology, such as the CRISPR/Cas9 system. development candidate. It is designed with the aim to precisely insert a healthy copy of the SERPINA1The gene which encodes the alpha-1 antitrypsin (A1AT) protein, commonly leading to lung dysfunction and liver disease. gene to potentially achieve steady, continuous expression of A1AT protein at therapeutic levels after a single dose. This approach aims to address AATD-associated lung disease and eliminate the need for sub-optimal weekly IV infusions of A1AT augmentation therapy or transplant in severe cases.
• NTLA-2003 is designed to knockout the mutant SERPINA1 gene to potentially reduce and prevent accumulation of mutant A1AT protein. This development candidate aims to address AATD-associated liver disease and eliminate the need for liver transplant in severe cases.

Hemophilia A and BSevere, rare genetic bleeding disorders, each caused by a different missing or defective clotting protein. Programs:

• In June 2020, Intellia and Regeneron expanded and extended their collaboration to research and develop CRISPR/Cas9-based treatments. Under the terms of two co-development and co-commercialization agreements, Intellia and Regeneron agreed to co-develop potential hemophilia A and BSevere, rare genetic bleeding disorders, each caused by a different missing or defective clotting protein. CRISPR/Cas9-based treatments using their jointly owned targeted transgeneA gene introduced into the genome by artificial (e.g. not found in nature) means. To perform targeted gene insertion, a transgene must be delivered to the cell nucleus and once there, fulfill the intended role of the gene, such as restoring protein production or recognizing an immune antigen. insertion technology. Regeneron is the lead party for both hemophilia A and hemophilia BSevere, rare genetic bleeding disorders, each caused by a different missing or defective clotting protein. development programs.
• These programs build on proprietary innovations developed by Intellia in its collaboration with Regeneron. Data presented in 2019 by Intellia highlighted the promise of Intellia’s technology by demonstrating the first CRISPR-mediated, targeted transgene insertion in the liver of non-human primates, which generated circulating human Factor IX, or FIX, protein at or above normal levels necessary to treat hemophilia BSevere, rare genetic bleeding disorders, each caused by a different missing or defective clotting protein., a severe genetic bleeding disorder. View Press Release

To keep up with our progress, check out our pipeline.