Glossary

Also known as AML. Cancer of the blood and bone marrow that is rapidly fatal without immediate treatment, and is the most common type of acute leukemia in adults.

Also known as AAV. AAVs are small viruses used to transport genetic code to target cells and are commonly used in traditional gene therapy. Intellia is combining AAVs with LNPs to develop a CRISPR/Cas9-based approach for targeted gene insertion, which could overcome challenges of AAV gene therapy.

Cell therapy comprising immune cells collected from healthy donors, rather than the patient, and then modified ex vivo (or outside the donors or patient’s bodies) to restore their function or add therapeutic properties, for example, to target specific cancer cells. After modification, cells are administered to the patient.

Also known as AATD. A genetic disorder with multiple manifestations, including lung dysfunction and progressive liver disease.

A protein component of the immune system that circulates in the blood and recognizes and fights pathogens. Over time or through administration of a vaccine, the body can build immunity through the production of antibodies to protect against pathogens in the future.

Antigens are unique to different pathogens, which include viruses, fungi and abnormal cells such as tumor cells. Antigens alert the immune system to foreign substances not recognized by the body, leading to immune responses like destruction of abnormal cells or production of antibodies.

ATTR 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.

Cell therapy created by genetically modifying a patient’s own immune cells ex vivo (or outside the patient’s body) to restore their function or add therapeutic properties, for example, to target specific cancer cells. After modification, cells are produced in large quantities and administered to the patient.

A peptide released from the biological pathway involving the KLKB1 gene and kallikrein activity. A reduction of kallikrein activity achieved through knockout of the KLKB1 gene is expected to correlate with a decrease in bradykinin activity. In turn, this decrease in bradykinin activity is expected to prevent the activation of endothelial cells that causes vascular leakage and angioedema in HAE patients.

CAR-T cell stands for chimeric antigen receptor (CAR) T cell therapy. This therapy type modifies  immune cells (T cells) to express a receptor on their surface that recognizes and binds to molecules (antigens) on the surface of malignant or cancerous cells. Once the receptor binds to a tumor antigen, the T cell is activated to attack the malignant cells.

Type of therapy where engineered cells are transferred into a patient’s body to grow, replace or repair damaged tissue, or perform another desired function. Cells used in these therapies may originate from a healthy donor (allogeneic cells).

A common type of cell therapy is blood transfusions, where red blood cells, white blood cells and platelets from one or more donors are transferred into the body of a patient.

A 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.

Also known as a CTA. Documentation required by regulatory authorities in many countries outside the U.S. seeking authorization to move from preclinical (animal) studies to clinical (human) trials to investigate an experimental treatment. A CTA is considered a regulatory authority equivalent to an Investigational New Drug (IND) application in the U.S.

Adapted 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 system to make specific changes in the DNA of humans, other animals and plants.

CRISPR 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.

Acronym for deoxyribonucleic acid, the hereditary material in humans and almost all other organisms. DNA can be found in the cell nucleus and contains the genetic instructions for the development, functioning, growth and reproduction of all known organisms. Nearly every cell in a person’s body has the same DNA.

Used to describe gene edits or protein expression sustained over a long period of time. Durability is an important indicator of the permanence of cell, gene and genome editing therapies, specifically the ability to result in a lasting change to the gene edits or effects of the therapy (e.g. protein reduction or protein restoration, depending on the disease).

An outcome of a clinical trial measuring a direct clinical benefit, such as safety, survival, decreased pain or the absence of disease. Clinical trials typically have both primary and secondary endpoints. When clinical trials accomplish the goals set forth in the study design, results are said to have “met their endpoints.”

Also referred to as a cell therapy. In an ex vivo therapy, cells are removed from the body for modification. Modification is done by administering therapy directly to the cells before they are returned to the body. In the case of ex vivo CRISPR/Cas9 therapies, CRISPR/Cas9 is used to modify cells to repair them to their desired functions. The engineered cells are then administered to the patient so they can treat a particular disease.

Also known as F9 gene. F9 is the gene that produces the FIX protein and is the target for Intellia and Regeneron’s hemophilia B targeted gene insertion experimental treatment.

Also known as FIX protein. FIX is a blood-clotting protein that is missing or defective in hemophilia B patients. Intellia and Regeneron’s hemophilia B experimental treatment aims to restore protein production resulting in FIX activity levels that are therapeutically effective, to halt disease symptoms and progression.

Also known as gene or DNA sequencing. Researchers use sequencing to determine the order of the four chemical bases that comprise a DNA molecule. Genes are made of DNA and determine how your body develops and function. Machinery in cells uses the sequence of a gene as the instructions to make a protein.

Type of therapy where healthy genetic code is incorporated into the patient’s body with the goal of treating or preventing disease, reducing further damage and pain or potentially curing the patient. If a mutated gene causes a protein to function poorly, gene therapy may be able to restore the function of the protein.

Precise gene insertion has the potential to overcome limitations of traditional gene therapy that uses adeno-associated virus (AAV) or lenti/retrovirus to deliver genetic code to its target.

A 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.

Also called gene editing. Genome editing collectively refers to a set of technologies, including CRISPR/Cas9, that can be used to cut and modify DNA. Genome editing uses systems to make the DNA change inside the cell. These cells can be edited in the body (in vivo) or outside the body (ex vivo) from a patient or donor.

Germ cells are reproductive cells in the body (sperm or eggs). These cells unite with one from the opposite sex to form new individuals.

Type of gene editing where genetic changes happen in all cells and can potentially be passed down to future generations. These alterations can be achieved within germ cells, or reproductive cells, such as egg and sperm.

Also known as GvHD. Condition in which a bone marrow or stem cell transplant or allogeneic cell therapy view the recipient’s body as foreign, and the donated cells attack the recipient’s body.

The engineering used to create Intellia’s T cell therapy development candidate is expected to result in lower reactivity against unwanted targets on normal tissues that could lead to toxicities, including GvHD.

Also known as gRNA. gRNA is one of two components comprising Intellia’s CRISPR/Cas9 gene editing system. Intellia researchers are applying this modular system to several experimental medicines by changing only the gRNA sequence to reprogram for a specific genetic target.

Severe, rare genetic bleeding disorders, each caused by a different missing or defective clotting protein.

Surgical resection, or removal, of the liver. A partial hepatectomy, where part of the liver is removed is also known as a PHx. Livers can usually regenerate on their own following a hepatectomy.

Also 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.

Meaning “within the living”, this type of therapy is administered directly into the patient, targeting the cells and editing the genome from inside the body.

In a clinical trial setting, informed consent means that patients considering volunteering to enroll receive information and consent to the purpose of the research, including their role and how the trial will work. Several healthcare team members will review an informed consent form with a volunteer prior to conducting study procedures.

Insertion of a new DNA sequence into the genome to manufacture a desired protein using a gene editing technology, such as the CRISPR/Cas9 system.

In 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).

Also known as an IND or IND application. Companies like Intellia submit an IND to begin testing of investigational therapies in humans in the U.S. An IND is equivalent to a CTA, the regulatory application required in many countries outside the U.S. to begin clinical testing.

Reduction of protein, with the goal of achieving a therapeutic effect, as a result of a gene or genome editing therapy is often known as protein knockdown.

Inactivation/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.

Also 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.

Also known as blood cancers or hematological malignancies. Cancers like leukemia, lymphoma and myeloma that originate in blood, bone marrow and lymph.

Also known as mRNA. mRNA, which encodes the Cas9 protein, is one of the components comprising Intellia’s CRISPR/Cas9 LNP delivery system. Intellia researchers are applying this modular LNP system to several experimental treatments by changing only the gRNA sequence.

Modifying multiple genes simultaneously.

Researchers often use a murine, or mouse, model for early preclinical testing of experimental treatments. Studies typically progress from a murine model to testing in either a higher rodent species, such as rats, or to NHPs.

Also known as NHP. Preclinical studies advance from rodent to higher species, such as NHP, studies prior to entering clinical (human) testing. Due to their physiological similarity to humans, NHPs are used for research because they are usually the next best model to humans to investigate whether an experimental treatment is ready to enter clinical trials.

A pathogen is any of any foreign substance that the immune system does not recognize and tries to fight off by producing an immune response against it. The immune system identifies these foreign substances through antigens unique to each pathogen.

Sometimes paired with pharmacokinetics to form the abbreviation, PKPD. Pharmacodynamics is how your body reacts to the experimental treatment. PKPD is often part of an objective or endpoint of a clinical trial and is usually analyzed through a blood sample.

Sometimes paired with pharmacodynamics to form the abbreviation, PKPD. Pharmacokinetics is how an experimental treatment moves through the body. PKPD is often part of an objective or endpoint of a clinical trial and is usually analyzed through a blood sample.

Also 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.

Using a combination of tissue engineering and molecular biology to treat genes – the root causes of gene-based diseases and disorders. This new field brings together biology, chemistry, computer science, engineering, genetics, medicine, robotics and other fields to find the solution to some of the most challenging health issues in medicine.

Also known as a regulatory agency. The U.S. FDA and the U.K. MHRA are examples of local regulatory authorities responsible for protecting human health. Drug developers like Intellia must seek regulatory approval prior to starting a clinical trial and subsequent product approval.

Correction of “misspelled” disease-driving DNA sequence using a CRISPR/Cas9-based gene editing therapy.

Performing more than one gene edit, in sequence as part of a single process or therapy – for example, multiple knockout edits or a knockout edit followed by a targeted gene insertion.

Intellia has developed a proprietary sequential genome editing process in primary human T cells that can lead to the knockout of multiple genes.

The gene which encodes the alpha-1 antitrypsin (A1AT) protein, commonly leading to lung dysfunction and liver disease.

Refers to tumors that are solid, vs. liquid, in cancers such as ovarian cancer, glioblastoma, lung cancer and mesothelioma. These are examples of cancers that Intellia’s lead WT1 TCR may have the potential to target.

Type of gene editing performed in somatic cells to induce non-heritable changes. These edits alter the cells that cannot contribute to the germline and thus cannot be passed down to offspring.

Non-reproductive cells in the body. Most genetic diseases manifest in somatic cells. The DNA in these cells is non-heritable, which means that somatic cell genome editing affects only the patient and will not be genetically transmitted to future children. Examples of these types of cells are cells that make up the retina, liver, heart, etc.

Cells from which all other cells with specialized functions are generated. Under the right conditions (in the body or laboratory), stem cells divide to form more specialized cells. Stem cells can be guided into becoming specific cells that can be used to regenerate and repair diseased or damaged cells in people.

Refers to a drug or therapy that uses substances that are injected into the body and travel through the bloodstream to deliver the therapy to the area of interest. The NTLA-2001 Phase 1 clinical trial is the first time a CRISPR/Cas9 gene editing treatment will be delivered through a vein of the human body to edit genes.

Type of white blood cell, or leukocyte, essential to the immune system. Intellia is engineering T cells against specific cancer antigens.

Antigen receptor found on the T cell membrane that can efficiently recognize antigens that arise on the surface of a cell or from within a cell. Intellia’s T cell therapy development candidate is wholly owned and utilizes a TCR-directed approach to target the WT1 intracellular antigen for the treatment of AML.

A 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.

Translocation is when a portion of a chromosome fuses to a different chromosome. Genetic translocations are typically unintended and, in specific circumstances, may have negative consequences, such as causing serious disorders like cancer.

Also 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.

Transthyretin (ATTR) amyloidosis resulting in severe and permanent peripheral nerve damage, and manifested through symptoms that include tingling and numbness in legs and feet, difficulty walking, limb weakness and pain. Polyneuropathy is also known as peripheral neuropathy.

Intellia’s first therapeutic candidate, NTLA-2001, is being studied in the clinic as a single-course treatment for hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN or hATTR-PN).

Also known as TTR gene. Responsible for production of the TTR protein. The disease, ATTR, 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.

Also 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.

Also known as WT1. Protein that in most AML cells and also in a variety of solid tumors is expressed at levels high above normal expression levels. This overexpression makes WT1 an attractive tumor target. Intellia’s T cell therapy development candidate utilizes a TCR-directed approach to target the WT1 intracellular antigen for the treatment of AML.