Treatment of rare genetic diseases using CRISPR has entered the ‘countdown’. In particular, the successful method of treating genetic diseases by directly injecting CRISPR into the human body is an issue. According to the World Health Organization (WHO), there are more than 10,000 genetic diseases caused by a single gene mutation. Rare diseases, such as hemophilia, sickle cell anemia, and Huntington’s disease, are numerous and number in the millions. CRISPR injection technology is considered as a solution to treat these incurable genetic diseases.
Proven efficacy in hereditary angioedema clinical trial
CRISPR is an enzyme that cuts and corrects a specific region in the DNA containing the genetic information of animals and plants. It is a DNA-cleaving enzyme derived from the immune system of bacteria, and is a technology that allows desired properties to be expressed. On June 28, 2012, Professor Jennifer Doudna’s team at the University of California, Berkeley, USA published the first presentation in the international scientific journal ‘Science’.
Ten years later, CRISPR has become one of the hottest technologies in modern biology. This is because treatments for genetic diseases that were unthinkable before CRISPR were being tried are being tried. Professor Daudna, who developed it, and Dr. Emmanuel Charpentier of France, were awarded the 2020 Nobel Prize in Chemistry.
In particular, CRISPR has recently gained prominence in the treatment of patients suffering from fatal hereditary angioedema. Intellia, an American biotechnology company that directly injected CRISPR into the blood of three patients and conducted a phase 1 clinical trial, is the leading player. Hereditary angioedema is mainly caused by mutations in the gene (C1-inhibitor) located on chromosome 11. Due to this, a deficiency or dysfunction of a substance called ‘C1 esterase’ appears. In that case, the level of ‘bradykinin’, a vasodilator hormone, increases, causing severe swelling of the legs, arms, face, and neck. Violation of the airways may result in asphyxiation. In case of edema in the gastrointestinal tract, it causes vomiting and diarrhea.
Intellia’s team used CRISPR to treat hereditary angioedema. A low-dose CRISPR (enzyme) and messenger RNA (mRNA) that will guide it to target cells are wrapped in lipid nanoparticles and injected directly into the patient’s bloodstream. Since then, CRISPR, which has safely reached the target cells, removed the related (mutant) gene so that the toxic protein (Kallikrein) that increases the bradykinin level is not expressed. As a result, the blood levels of kallikrein in the three patients decreased by an average of 65% in 8 weeks.
Patients with hereditary angioedema usually have symptoms at least once a week and as long as 2-3 times a year. However, with just one CRISPR injection, two patients who had edema 2-3 times a month disappeared, and the patient who experienced swelling up to 7 times a month also stopped symptoms after 10 weeks. Professor Hillary Longhurst at the University of Auckland, New Zealand, explains that the symptoms did not return to patients who did not take the medications they were taking.
In addition, three other patients who subsequently received high-dose CRISPR had their kallikrein levels dropped by 92%. The gene-editing treatment CRISPR effectively served as a cure. Of course, drug treatments also help prevent diseases by blocking the protein kallikrein, which increases bradykinin levels. However, because CRISPR permanently removes the kallikrein-expressing gene, patients do not need to use the drug for the rest of their lives.
Professor Longhurst says these results demonstrate that the success achieved with CRISPR injection is a reproducible technique, not an aberration, and is early evidence that CRISPR gene editing in the body can be a safe and effective way to treat disease.
In most cases, hereditary angioedema is inherited in an autosomal dominant manner. The prevalence is about 1 in 50,000 people. About 25% of patients have sporadic outbreaks without a family history. It usually first appears in late adolescence or early adolescence. Patients who received treatment for hereditary angioedema this time said, “CRISPR has changed my life.
Phase 2 clinical trial in progress
This is not the first case of gene editing by directly injecting CRISPR into a human body. Last year, Intellia’s team tried to treat symptoms caused by amyloid accumulation by injecting CRISPR into a patient with a rare genetic disorder called transthyretin amyloidosis (ATTR). However, it is not yet known whether the patients’ symptoms have improved. Therefore, this result is the first case where CRISPR gene-editing therapy has proven efficacy in human clinical studies.
Transthyretin amyloidosis is a disease in which amyloid deposits in various tissues or organs due to dysfunction of transthyretin (TTR), a transport protein that naturally circulates in the blood. When amyloid deposits in the peripheral nerves, polyneuralgia occurs, and when amyloid deposits in the heart, cardiomyopathy occurs.
CRISPR treatment is divided into the method of directly injecting genetic material into the patient’s body (in-vivo) and the method of collecting the patient’s cells, undergoing gene editing in the laboratory, and then injecting the cells back into the body (ex-vivo). . Previously, the indirect method ex-vivo was mainly used. That’s because it was much more difficult to get CRISPR into a specific organ or cell inside the body through an intravenous injection.
Since the in-vivo method injects the gene scissors directly into the body, there is no need for in vitro manipulations such as extracting, transforming, or culturing the patient’s cells like ex-vivo. Therefore, the advantage is that time and cost can be reduced. However, if it is not accurately delivered to the target cell, it may cause side effects. This technology is used to semi-permanently treat rare genetic diseases.
On the other hand, the advantage of the ex-vivo method is that it can reduce side effects caused by random reactions other than the target organ or tissue cells. However, the disease to which the treatment can be applied is limited, and there are disadvantages in that it takes a lot of time and money compared to the in-vivo method. It is mainly used for the treatment of immune cancer or autoimmune diseases. Intellia has developed both methods.
Intellia is currently testing a mid-range capacity CRISPR. In the phase 2 clinical trial to determine how much dose should be injected to have a large therapeutic effect, it plans to enroll more patients. Intellia CEO John Leonard emphasizes that if the phase 2 clinical trial is successful, CRISPR will become a breakthrough treatment for fundamentally treating rare genetic diseases. We look forward to the success of the research team’s Phase 2 clinical trial.