Intellia advances CRISPR/Cas9 delivery to treat sickle cell

Intellia CEO John Leonard headshot
Intellia CEO John Leonard, M.D. (Intellia Therapeutics)

Intellia Therapeutics has presented preclinical data on its bone marrow-tropic delivery system for in vivo genome editing. The study moves Intellia a step closer to its goal of systemically delivering CRISPR/Cas9 to treat diseases such as sickle cell.

CRISPR Therapeutics and Vertex have provided early clinical validation of the use of ex vivo genome editing to treat sickle cell. However, Intellia sees downsides to the ex vivo approach, such as the complexity of its manufacturing process and toxicity of the conditioning regimen, which will restrict its use to highly selected patients with severe disease in a limited number of geographies.  

In theory, in vivo editing could eliminate those challenges. Rather than harvest and edit cells, users of the in vivo approach will infuse a formulation, removing the complexity associated with autologous treatments. Equally, avoiding myeloablation could make the treatment safer than ex vivo therapy.

Pursuit of those benefits led Intellia to develop lipid nanoparticles designed to get CRISPR/Cas9 to the targeted sites for genome editing in the body, specifically the bone marrow. So far, researchers have had most success targeting the liver, making the Intellia project a test of the potential to expand in vivo genome editing to other organs.

In mice, Intellia saw dose-dependent editing in whole bone marrow and hematopoietic stem and progenitor cells one week after dosing. Editing levels in mice that received the mid- and high-dose were beyond the threshold Intellia thinks it needs to clear to cure sickle cell. The persistence of editing out to one year suggests durable effects can be achieved from a single course.

Giving mice up to four doses, something that could be possible in humans with the nonviral delivery platform, further increased editing. Intellia said the support for multidosing could potentially enable a “‘treat-to-target’ therapeutic approach.”

The biotech is still some way from validating that idea in humans. The next step is to test the therapy in nonhuman primates. Intellia is taking the candidate through preclinical using a grant from the Bill & Melinda Gates Foundation.