In race for in vivo sickle cell cure, Intellia unveils (very) early proof-of-concept
Vertex and CRISPR Therapeutics have shown they can use the gene editing tool to cure, for at least a couple years, a handful of patients with sickle cell disease and are now entering late-stage development.
It’s a major advance, but it comes with the same caveats that have plagued other gene therapies for sickle cell. You have to give patients what amounts to a bone marrow transplant: a laborious, expensive and occasionally risky procedure that involves removing stem cells from their marrow, editing them in a facility and then re-injecting them. Any company that could find a way to edit cells with a simple IV infusion could make those older approaches obsolete.
Intellia, one of the first big CRISPR companies, unveiled one new approach to reaching that simple IV at a scientific conference Wednesday. The biotech used custom lipid nanoparticles — those now–famous tiny bubbles of fat — to carry CRISPR into the bone marrow of mice and edit stem cells there. After repeated dosing, the company’s scientists said they were able to edit more than enough cells to provide a functional cure for sickle cell.
“This new data supports the possibility of delivering a safer solution to treat blood disorders, including sickle cell disease, by avoiding the need for bone marrow transplantation,” Intellia CEO John Leonard said in a statement.
The results provide a (very) early proof of concept for an approach the Gates Foundation has already bet on. In the fall, they awarded Intellia a grant of $2.8 million to develop their lipid nanoparticle CRISPR system for sickle cell disease and HIV, another deadly disease that might be cured by editing stem cells in the bone marrow.
Still, Intellia is far from alone in that race. Their cross-town gene editing rivals CRISPR Therapeutics also received a similarly sized grant from the foundation to develop lipid nanoparticles that target the bone marrow, although theirs is exclusively HIV-focused. And others, most notably Fred Hutch’s Hans Peter-Kiem and University of Washington’s André Lieber, have gone much further on an approach that uses a modified virus to deliver a gene for functioning hemoglobin directly into patients’ stem cells, showing proof-of-concept in monkeys. A well-heeled biotech called Ensoma, launched last month, is developing their approach further.
Intellia, though, is the only company to date to use lipid nanoparticles for gene editing or gene therapy in patients. Last year, they started dosing patients with a CRISPR therapy meant to knock out the central gene in a rare liver disease.
While gene therapy companies have relied largely on modified viruses to deliver new genes into human cells, gene editing companies have relied much more heavily on nanoparticles. CRISPR machinery is often too large and clunky to fit into those viruses. And although gene therapy companies need viruses to get the therapeutic gene to stay inside a cell for years, CRISPR companies just need their therapy to hit once and permanently alter the DNA.
The biggest hurdle is that most lipid nanoparticles go directly to the liver. Companies have spent hundreds of millions of dollars trying to develop ones that are targeted to other regions of the body, such as the brain or muscle. Beam Therapeutics recently spent up to $420 million to purchase an academic spinout devoted solely to building targeted lipid nanoparticles.
Intellia developed lipid nanoparticles that target the bone marrow. They predict, based on studies from early sickle cell gene therapies, that they would need to edit 20% of cells to offer a functional cure. After a single dose into mice, they were able to edit about 10%.
Unlike other delivery methods, lipid nanoparticles can be given repeatedly. After a second dose, they had edited about 25% of bone marrow cells. After the 4th dose, they had edited more than 40% of cells.
In a note to investors, Chardan’s Geulah Livshits said the data were quite early but encouraging.
“We could envision such strategies emerging in coming years and, while many unknowns remain, see Intellia’s early data as a step in that direction,” she said.