The first-of-its-kind gene therapy dramatically reduced the levels of misfolded proteins in some clinical trial participants for up to six months and lowered levels in all participants for up to one year.
Researchers have successfully deactivated the gene in human patients by treating them with CRISPR gene-editing technology, clearing patients’ blood of the toxic protein by up to 93 percent for some patients up to six months after initial treatment. The researchers detailed the findings in a press release, phase 1 clinical trial update and data slides on Monday (Feb. 28).
the study, told Science.
See “CRISPR Thumbs Towards Clinic”
The 15 patients enrolled in a clinical trial by drug companies Intellia Therapeutics and Regeneron Pharmaceuticals have an inherited gene mutation called transthyretin (TTR) amyloidosis, a progressive neurological disease that causes numbness, nerve pain and heart failure.
The mutation causes the liver to produce a misfolded version of the protein transthyretin, which clumps into insoluble amyloid fibrils that the body cannot clear. These accumulate in the heart, muscles, internal organs and nerves, causing damage and preventing normal function.
Healthy transthyretin helps transport vitamin A (retinol) throughout the body, but it has a “limited and specific normal function,” meaning knocking it out has limited physiological effects, according to a clinical study published last year in the New England Journal. medicine.
The researchers behind the study tell Science that they hope their CRISPR-based treatment will be the first one-time treatment for TTR and provide long-term benefits. In contrast, existing treatments must be administered regularly. Alnylam Pharmaceuticals’ Onpattro must be administered once every three weeks to achieve therapeutic benefit. Ionis Pharmaceuticals’ Tegsedi must be administered weekly.
Last year, Intellia and Regeneron began injecting patients with a CRISPR-Cas9 system, enclosed in fat droplets, that contained the genetic instructions to remove the dysfunctional TTR gene from cells, Science reports. The droplets contain a guide RNA that targets the gene that produces TTR and another strand of RNA that guides the Cas9 cleaving gene into liver cells.
After the Cas9 protein cuts the part of the DNA that codes for TTR, the body’s native gene repair system glues the DNA back together, but does so imperfectly, truncating and knocking out the TTR gene.
At the time, the drug companies reported that blood levels of the protein dropped dramatically in six patients a month after the injection
Since the publication of the first report, the researchers have added nine additional participants to their ongoing clinical trial. Patients received one of four doses of treatment. Researchers now report that TTR levels in patients who received a single treatment remained stable — at 7 to 59 percent of pre-study levels 2 to 12 months after treatment — with individual patients varying depending on which doses of CRISPR treatment they received. Patients who received the highest dose experienced a 93 percent reduction in TTR levels one month after treatment, which remained stable for at least six months after treatment.
Patients receiving the lowest dose, the six patients in the initial cohort, initially had a 52 percent reduction in protein levels, but that number dropped to 41 percent after a year, the researchers said. The researchers also reported no serious side effects at any doses. But The Washington Post says more data is needed to show the treatment won’t have any dangerous side effects or cause off-target DNA damage.
Based on preclinical tests in mice and monkeys, the researchers expected the levels of the protein to remain low in humans. However, liver cells are replaced every 200 to 300 days, so there is a chance that patients’ livers will start producing misfolded TTR again.
Scientists are not sure if the treatment will improve symptoms or simply stop the progression of the disease. The researchers have not yet collected data on whether patients who already experienced pain and numbness throughout their body before treatment experienced a reduction in symptoms.
But researchers remain optimistic because the drugs currently used to treat TTR amyloidosis improve symptoms, even though they only reduce TTR levels in the blood to 80 percent of normal.
Correction (March 4): The article has been updated to reflect that the study updates were released on February 28, not March 1. The article has also been updated to reflect that the researchers have not yet reported clinical results. The article was clarified to reflect that Intellia had updated an ongoing clinical trial in which researchers first published that it was possible to disable the disease-causing gene withA scientist regrets mistakes.