The CRISPR Gene Editor excels at fixing disease mutations in cells grown in the laboratory. But use CRISPR to cure most people with genetic diseases it requires you to overcome a huge obstacle: insert the molecular scissors into the body and make them slice the DNA in the tissues where it is needed.
Now, at first medical, researchers have injected a CRISPR drug into the blood of people born with a disease that causes fatal nerve and heart disease, they have shown that in three of them it almost stopped the production of toxic proteins by their livers.
Although it is too early to know whether CRISPR treatment will alleviate symptoms of the disease, known as transthyretin amyloidosis, preliminary data reported today are generating excitement for what it could be a one-time and permanent treatment. “These are surprising results”, says genetic editing researcher and cardiologist Kiran Musunuru of the University of Pennsylvania, “Exceeds all my expectations.”
The work also marks a milestone in the race to develop treatments based on messenger RNA (mRNA), the instructions for building proteins naturally produced by cells. Synthetic mRNAs power two COVID-19 vaccines given to millions of people to fight the coronavirus pandemic, and many companies are working on other vaccines and mRNA drugs.
The new treatment, which includes an mRNA that encodes one of the two components of CRISPR, “The convergence of CRISPR and mRNA fields begins”says the cardiovascular researcher Kenneth Chien of the Karolinska Institute, co-founder of Moderna, which produces one of the COVID-19 vaccines and is also developing mRNA drugs
CRISPR: the study
The CRISPR clinical trial aims to inactivate a mutated gene that causes liver cells to churn out misfolded forms of a protein called transthyretin (TTR), which builds up on the nerves and heart and leads to pain, numbness and heart disease.
The resulting condition is relatively rare, and an approved drug, patisiran, can stabilize it. But researchers at veteran biotech Regeneron Pharmaceuticals and startup Intellia Therapeutics saw it as a good proof of principle for the injectable CRISPR treatment they were developing.
Last year, researchers used CRISPR to activate a fetal form of hemoglobin to correct sickle cell anemia. Treatment involved removing a patient’s diseased blood stem cells, editing them with CRISPR in a dish, and then reinfusing them into the body.
A study is also underway that tests a direct injection of a virus that encodes components of CRISPR into the eye to treat a condition that causes blindness. But treating most other diseases somehow means injecting the components of CRISPR, or the genetic instructions for them, into the blood and having the therapy target an organ or tissue – a huge challenge, but potentially easier in the process. liver because it absorbs foreign particles.
In the CRISPR study, four men and two women with transthyretin amyloidosis aged 46 to 64 were injected with a lipid particle that carried two different RNAs: an mRNA that encodes the Cas protein, the CRISPR component that cuts DNA. and a guide RNA to direct it to the gene for TTR. After Cas makes his cut, the cell’s DNA repair mechanism heals the break, but imperfectly, eliminating the activity of the gene.
After 28 days, three men who were given the higher of two doses of the treatment had a drop 80% to 96% of TTR levels, at or above the average of 81% with patisiran, the team reports today in the New England Journal of Medicinale.
“The data are extremely encouraging”says trial leader Julian Gillmore of University College London, who also presented the study today at the Peripheral Nerve Society’s annual online meeting. “It could be the first curative treatment for this disabling and life-threatening hereditary disease”says neurologist David Adams of the University of Paris-Saclay, who conducted the studies for the patisiran.
It may take months for patients receiving CRISPR treatment to see their symptoms diminish, but they have reported few short-term side effects. Problems could emerge over time: CRISPR could potentially make cuts in the wrong location of DNA (and in non-liver cells), triggering cancer or other problems.
But the lipid-encapsulated mRNA approach is potentially safer than using viruses to carry genetic instructions to encode a modification protein and drive RNA into cells, a tried and true approach that others are pursuing to systemic treatments. Those genes can persist in cells, continuing to create the gene editor long after it has done its job. In reverse, “The beauty of mRNA is that after it is gone”says Chien.
The study paves the way for the treatment of other liver diseases with CRISPR, either by eliminating a gene or, more challenging, by modifying it with the help of a DNA template. The latter approach could also be used for turning the liver into a factory to produce an enzyme needed in other parts of the body.
Jennifer Doudna of the University of California, Berkeley, who shared a Nobel Prize last year for discovering CRISPR and co-founding Intellia, he sees even greater prospects. The new job, he says, is “A fundamental first step in being able to inactivate, repair or replace any gene that causes disease, anywhere in the body.”