Preliminary results from an ongoing trial by Intellia Therapeutics show that a drug based on CRISPR-Cas9 can be delivered to the body to target the liver and reduce expression of the gene responsible for transthyretin amyloidosis (ATTR ).1 This is the first clinical trial demonstrating the success of gene editing in vivo; the results suggest that it may be possible to safely modify the genomes of the body’s cells.
“For in vivo delivery, the goal is for you to be able to deliver CRISPR as a drug to the patient,” said Laura Sepp-Lorenzino, Scientific Director of Intellia Therapeutics.
ATTR is characterized by a misfolded version of the protein transthyretin (TTR) that accumulates in the heart, nervous system, and kidneys. Patients generally experience pain, weakness, and an inability to control basic bodily functions. “It’s a really appalling disease,” said Julian Gilmore, a medical researcher at the National Amyloidosis Center at University College London, who led the trial.
Previous studies have found a potentially straightforward treatment route: reducing the amount of circulating TTR to reduce symptoms of the disease. Lower TTR levels slow down protein buildup. Some previously approved drugs do this with small interfering RNAs or antisense oligonucleotides that help break down or sequester the RNA encoding TTR.2.3 But these treatments require pretreatment followed by weekly or monthly administration of the drug, which causes unpleasant side effects. These treatments often fail to cure the disease; As symptoms improve, many patients die within 10 years of diagnosis.
ATTR can cause the TTR protein to build up in various organs, especially the heart (shown in yellow).
The potential to treat ATTR by simply reducing TTR – and the limited effectiveness of previous attempts to do so – made the disease an ideal scenario for CRISPR-Cas9, Gilmore said. Molecular scissors could reduce TTR levels by disrupting the gene that codes for it. This snip is a more potent way to dampen expression, and a single infusion of CRISPR alters cells to lower TTR in perpetuity, which could also repair previous damage. “Intellia’s goal is not only to stop the progression of the disease, but potentially to be able to come back and gain function,” said Sepp-Lorenzino.
Using CRISPR to modify cells directly in the body, rather than removing and modifying cells in the lab and sending them back to the patient, is no small feat. Here ATTR offered a unique advantage. TTR is produced almost exclusively in the liver, an organ that can be specifically targeted for drug delivery. Wrapping a drug in a fat bubble called a lipid nanoparticle causes it to travel directly to the liver, allowing efficient delivery and reducing off-target effects.
Intellia’s lipid nanoparticles contain guide RNA targeting TTR and mRNA encoding the Cas9 endonuclease which makes the genomic cuts. In their ongoing Phase I trial, they administered the drug (NTLA-2001) to six patients with nerve damage resulting from ATTR. Half of the participants received a lower dose and half received a higher dose. Twenty-eight days after treatment, no serious side effects were reported.
“I don’t think there is any question based on the results that the edition not only works, but works extremely well,” said Kiran Musunuru, cardiologist at the University of Pennsylvania and co-founder of the biotechnology company CRISPR Verve Therapeutics, which was not involved in the study.
TTR levels were halved in the lower dose group and decreased by 80 to 96 percent in the higher dose group. The goal is to reduce TTR from 90 to 95 percent, Gilmore said. For comparison, existing therapies reduce its presence by about 80%. He was surprised to see that some patients in the trial were already reaching these desired levels. “This opens up the real possibility that these patients will actually improve,” Gilmore said. Future plans are to continue increasing the dosage, which Gilmore says will lead to better results for more patients.
While the first results of the trials focus on patients with nerve damage, another class of patients mainly show cardiac symptoms. Gilmore believes that these patients may benefit even more from this treatment because the buildup of amyloid in the heart is particularly sensitive to TTR levels. There are plans to test the drug in these patients in the next phase of the trials.
If the drug continues to be successful in clinical trials, Sepp-Lorenzino expects treatment of ATTR patients to one day be as simple as a two-hour infusion of lipid nanoparticles in an outpatient center.
“It’s going to shift from a model where we take pills every day or injections every few weeks for long periods of time,” Musunuru said. “Gene editing therapies are going to turn that model into a model where you have unique therapies.”
Demonstrating the ability to deliver genome editing machines to the liver potentially opens the door to editing any gene in the liver and treating more conditions. Intellia is already working on another CRISPR drug in vivo for hereditary angioedema that inhibits a different gene in liver cells.
It will take more work to target other types of cells. For example, scientists can design lipid nanoparticles with specific molecules on their surface to interact with a target cell type. An in vivo clinical trial conducted by Editas, a biotechnology company designing therapies based on CRISPR, to treat a retinal degeneration disorder with virus-delivered CRISPR-Cas9 has also recently shown clinical benefit, although retinal edition no not read as clearly as TTR Levels.4
“If we think CRISPR-Cas9 is revolutionizing medicine, then what we need is to be able to deliver the drug to all the cells in the body that we want,” Gilmore said. “I think that’s the real challenge for a wider application of this technology.
- JD Gillmore et al., “CRISPR-Cas9 gene editing in vivo for transthyretin amyloidosis,” N Engl J Med, 385 (6): 493-502, 2021.
- D. Adams et al., “Patisiran, a Therapeutic RNAi, for Hereditary Transthyretin Amyloidosis”, N Engl J Med, 379 (1): 11-21, 2021.
- MD Benson et al., “Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis”, N Engl J Med, 379 (1): 22-31, 2021.
- J. Mullen et al., “BRILLIANCE: A Phase 1/2, Single Ascending Dose Study of EDIT-101, an In Vivo CRISPR Gene Editing Therapy in Retinal Degeneration Linked to CEP290”, Presentation, September 29 2021.