The gene editor CRISPR excels at fixing disease mutations in lab-grown cells. But using CRISPR to treat most people with genetic disorders requires clearing an enormous hurdle: getting the molecular scissors into the body and having it slice DNA in the tissues where it’s needed. Now, in a medical first, researchers have injected a CRISPR drug into the blood of people born with a disease that causes fatal nerve and heart disease and shown that in three of them it nearly shut off production of toxic protein by their livers.
Although it’s too soon to know whether the CRISPR treatment will ease the symptoms of the disease, known as transthyretin amyloidosis, the preliminary data reported today are generating excitement about what could be a one-time, lifelong treatment. “These are stunning results,” says gene editing researcher and cardiologist Kiran Musunuru of the University of Pennsylvania, who was not involved in the trial. “It exceeds all my expectations.”
The work also marks a milestone for the race to develop treatments based on messenger RNA (mRNA), the protein-building instructions naturally made by cells. Synthetic mRNAs power two COVID-19 vaccines being given to millions of people to fight the coronavirus pandemic, and many companies are working on other mRNA vaccines and drugs. The new treatment, which includes an mRNA encoding one of CRISPR’s two components, “begins the convergence of the fields of CRISPR and mRNA,” says cardiovascular researcher Kenneth Chien of the Karolinska Institute, a co-founder of Moderna, which makes one of the COVID-19 vaccines and is also developing mRNA drugs.
The CRISPR clinical trial aims to deactivate a mutated gene that causes liver cells to churn out misfolded forms of a protein called transthyretin (TTR), which build up on nerves and the heart and lead 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 turn on a fetal form of hemoglobin to correct sickle cell disease or a related disease in several people. The treatment required removing a patient’s diseased blood stem cells, modifying them with CRISPR in a dish, and then infusing them back into the body. A trial testing a direct injection of a virus encoding CRISPR’s components into the eye to treat a condition that causes blindness is also underway. But treating most other diseases means somehow injecting CRISPR’s components, or genetic instructions for them, into the blood and having the therapy target an organ or tissue—a huge challenge, but potentially easier in the liver because it sops up foreign particles.
In the CRISPR trial, four men and two women with transthyretin amyloidosis between ages 46 and 64 were injected with a lipid particle carrying two different RNAs: an mRNA encoding the protein Cas, the CRISPR component that snips DNA, and a guide RNA to direct it to the gene for TTR. After Cas makes its cut, the cell’s DNA repair machinery heals the break, but imperfectly, knocking out the activity of the gene….
