Gates Foundation Funds Studies Into CRISPR/Cas9 Gene Editing for SCD

Intellia Therapeutics has received a grant from the Bill & Melinda Gates Foundation to develop sickle cell disease (SCD) treatments using the CRISPR/Cas9 genome editing technology, the company announced.

The approach, to be refined within living organisms (in vivo studies), aims to deliver a functional copy of the HBB gene into the genome of patients’ blood stem cells, located in the bone marrow, as a possibly superior option to stem cell transplants as a potential disease cure.

“We are excited to receive funding from the Gates Foundation to take the first steps toward development of a potential in vivo non-viral CRISPR/Cas9-based cure for SCD,” Laura Sepp-Lorenzino, PhD, chief scientific officer at Intellia’s, said in a press release.

SCD is caused by mutations in the HBB gene, which codes for the beta subunit of hemoglobin, a protein found in red blood cells that transports oxygen throughout the bloodstream. This mutation results in stiff and sickle-shaped red blood cells that often clog small blood vessels, causing symptoms that include anemia and episodes of severe pain.

A number of gene therapies that correct this genetic defect are being developed to treat SCD. But most require that a patient’s hematopoietic stem cells — cells that differentiate into all blood cell types, including red blood cells — are first collected and engineered in the lab to produce the functional gene, before being infused back into the bloodstream.

Intellia has been working on therapies that directly deliver the gene editing machinery to the cells of interest, allowing for genomic changes in cells inside living organisms.

The company uses the CRISPR/Cas9 gene-editing technology, a system modeled on a bacterial defense mechanism that scientists learned to co-opt and adapt, making it a highly targeted means of making changes, or edits, to the genome.

Using a lipid nanoparticle delivery system, as opposed to a modified virus as transport agent, the components of CRISPR/Cas9 system are delivered to target cells, where they are expected to make the required genomic edits.

Intellia is developing two gene-editing therapies that rely on this technology — NTLA-2001 for the treatment of familial amyloid polyneuropathy, and NTLA-2002 for hereditary angioedema. Both are designed to remove a disease-causing gene from the genome of liver cells.

With this grant, whose amount was not disclosed, Intellia will work on a similar approach for SCD. The goal is to deliver the CRISPR/Cas9 components to hematopoietic stem cells, and change their genome in a way that induces the production of a functional HBB gene. The funding will support preclinical studies validating the approach.

“Genome editing offers multiple opportunities to treat SCD as shown by encouraging emerging clinical data. Our goal is to deliver on the already demonstrated promise of CRISPR/Cas9, but avoid the severe complications of bone marrow transplantation that may limit the usefulness of current approaches,” Sepp-Lorenzino said.

“Intellia’s ambition is to use our non-viral in vivo platform to create an innovative treatment for blood disorders, that is scalable and can overcome the challenges inherent to ex vivo [outside a living organism] cell-based therapies for global diseases,” she added.

This pilot program is part of the Gates Foundation’s broader initiative to accelerate the development of safe, effective, and durable gene-based treatments in developing countries within the next seven to 10 years.