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In-Body Gene Editing Tested as Sickle Cell Treatment

Crispr graphic

(LJNovaScotia, Pixabay)

11 Mar. 2021. Tests with lab mice show the feasibility of editing genes in blood-forming stem cells in bone marrow as a potential treatment for sickle cell disease. Researchers from the biotechnology company Intellia Therapeutics in Cambridge, Massachusetts described their process yesterday at the virtual event, Keystone eSymposium: Precision Engineering of the Genome, Epigenome and Transcriptome.

Sickle cell disease is a genetic blood disorder affecting hemoglobin, a protein in blood that delivers oxygen to cells in the body. People with sickle cell disease have hemoglobin molecules that cause blood cells to form into an atypical crescent or sickle shape. That abnormal shape causes the blood cells to break down, lose flexibility, and accumulate in tiny capillaries, leading to anemia and periodic painful episodes.

Sickle cell disease is prevalent worldwide, with people in sub-Saharan Africa or of African descent most affected. A study in The Lancet estimates more than 300,000 people are born with sickle cell disease each year. In addition, the disease affects some 70,000 to 80,000 people in the U.S., including about 1 in 500 people of African descent.

Intellia is developing therapies with Crispr-Cas9 that remove disease-causing genes or mutations, repair genes with mutations found in small regions of DNA, and insert corrected or functioning genes when mutations are found in larger DNA regions. The company says its treatments are being designed to be either administered directly to patients, or delivered to cells taken from the patient, then cultured outside the body and transplanted back.

Crispr, short for clustered, regularly interspaced short palindromic repeats, is adapted from a natural process used by bacteria to protect against attack by viruses, where an enzyme that deactivates or replaces genes binds to targeted RNA molecules generated by the genome. The RNA molecules then guide the editing enzyme, known as Crispr-associated protein 9 or Cas9, to specific genes needing changes.

Produce healthy blood cells for nearly a year

In this case, Intellia’s Crispr therapy is designed to work in vivo, or inside the body. The company’s process packages and delivers edited genes in nanoscale bubbles of lipids or natural oils into blood-forming stem cells located in bone marrow. Many gene therapies today use benign viruses, such as adenoviruses, for delivery. For this study, the researchers tested delivery of genes edited with Crispr-Cas9 in lipid nanoparticles, rather than adenoviruses, into the bone marrow of lab mice.

The Intellia team found edited genes can be delivered with this method into blood-forming stem cells and whole bone marrow. The researchers tested delivery of edited genes at different dosage levels and found mid- to high doses could achieve desired therapeutic effects, with the effects lasting for nearly a year after delivery. In addition, the researchers found bone marrow in the mice receiving edited genes could produce healthy levels myeloid, B-, and T-cells.

In a separate set of tests, the Intellia team injected edited human stem cells in lipid nanoparticles in the tails of mice grafted with human blood-forming stem cells. The researchers found these so-called humanized mice could produce edited human blood-forming stem cells, offering a cross-species method of producing therapies for inherited blood disorders.

The researchers believe their process offers an alternative to bone marrow transplants for treating sickle cell disease. “This new data,” says Intellia president and CEO John Leonard in a company statement, “supports the possibility of delivering a safer solution to treat blood disorders, including sickle cell disease, by avoiding the need for bone marrow transplantation.”

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