Sickle cells illustration (Open Stax College, Wikimedia Commons, https://commons.wikimedia.org/wiki/File:1911_Sickle_Cells.jpg)
31 Mar. 2021. A clinical trial is set to begin that tests a direct form of gene editing with Crispr to correct inherited malfunctioning genes causing sickle cell disease. The trial is conducted by a group of three California universities, with University of California in San Francisco reporting that the Food and Drug Administration cleared the study to begin.
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.
Up to recently, editing the malfunctioning HBB or beta-globin gene responsible for sickle cell disease required more expensive and imprecise techniques. For example, edits are made in the gene to first reactivate fetal hemoglobin that regulates red blood cell production, or gene edits are delivered with benign viruses to blood forming stem cells in bone marrow where red blood cells originate. As reported by Science & Enterprise earlier in March, Intellia Therapeutics in Cambridge, Mass. is testing in lab animals direct delivery of Crispr gene-edits packaged in lipid nanoscale particles to blood forming stem cells to treat sickle cell disease.
Electronic pulses create pores in stem cells
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.
The new clinical trial is testing a process developed by the Innovative Genomics Institute, a genetics research center affiliated with UC San Francisco and UC Berkeley, with colleagues at UC San Francisco’s Benioff Children’s Hospital in Oakland and UCLA. Their technology, code-named CRISPR_SCD001, extracts a sickle cell patient’s blood forming stem cells, then sends mild electric pulses called electroporation into the cells that create temporary pores in the outer cell membranes. Those pores make it easier for the RNA guides in Crispr to reach the stem cells’ nuclei and correct the HBB genes.
Once underway, the early- and mid-stage clinical trial will enroll nine individuals with sickle cell disease, six adults and three adolescents, at Benioff Children’s Hospital and UCLA Medical Center. The team led by pediatric hematologist Mark Walters will extract individuals’ blood-forming stem cells, where they will be subjected to electroporation and Crispr gene edits in the UCLA gene manufacturing lab, then infused back into the patients.
The six adult participants will receive the first treatments, followed by the adolescents, with all participants tracked for 24 months. The study team is looking primarily for serious adverse effects from CRISPR_SCD001, but also a host of other safety and efficacy indicators, including rates of vascular pain episodes, over that period.
“This therapy,” says Walters in a UC San Francisco statement, “has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease.”
More from Science & Enterprise:
- Novartis, Gates Partner on Sickle Cell Gene Therapy
- Trial Results Show Gene Transfers Reverse Sickle Cell Disease
- Company Formed to Advance Sickle Cell Gene Therapy
- NIH, Biotech Partner on Electro-Aided Crispr for Sickle Cell
- Clinical Trials Okayed for Sickle Cell Gene Editing
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