CRISPR in the clinic
Mutations in the beta-globin gene affect the function of hemoglobin and cause the genetic disorders beta thalassemia and sickle cell disease. CRISPR is being used to turn on fetal hemoglobin (by disabling a gene that turns it off) in hematopoietic stem cells isolated from patients. Modified cells are reinfused into patients. Patients in the trials are doing well, and side effects appear limited to the bone marrow transplant chemotherapy regimen. The beta thalassemia trial, with initial data announced in November 2019, is the first to use an ex vivo (cells modified outside the body) CRISPR-based therapy to treat a genetic disease.
CRISPR is being used to modify tumor-killing T cells extracted from patients and then reinfused. One trial inactivated the PD-1 gene, which produces the protein target of certain immunotherapy checkpoint inhibitor drugs, in T cells from 12 patients with non-small cell lung cancer. The other added a CAR-T cell gene and used CRISPR to inactivate three genes that interfere with anti-tumor immunity in T cells from two patients with myeloma and one with sarcoma. Both trials met the goals of showing safety and tolerability, with results reported in February and April 2020. The lung cancer trial, which began in 2016, was the first to treat a patient with a CRISPR-based therapy.
Protein Folding Disorder
Transthyretin amyloidosis results from accumulation of the misfolded protein transthyretin (TTR) in the heart, nerves and other tissues. A CRISPR trial is using components to cut and disable the TTR gene, delivered in lipid nanoparticles in a single intravenous dose to patients with hereditary transthyretin amyloidosis with polyneuropathy. Lipid nanoparticles tend to accumulate in the liver, the primary site of TTR production. This is the first trial of a lipid nanoparticle delivery system and the first CRISPR therapy to be administered systemically to edit genes in the human body. The therapy was associated with only mild adverse events and decreased serum TTR protein concentrations, researchers reported in June.
Leber congenital amaurosis (LCA) is the most common cause of inherited childhood blindness.
LCA10, which accounts for about 20% of LCA cases, is caused by mutations in a photoreceptor gene. A CRISPR treatment composed of a viral vector carrying the CRISPR components is being injected directly into one eye of patient volunteers with LCA10 to correct the faulty photoreceptor gene. The first low-dose injections were completed in November 2020; results have not yet been released. The LCA10 trial is the first to test an in vivo CRISPR treatment, rather than an ex vivo treatment of cells that are returned to the patient.
Urinary tract infections (UTIs) are most often treated with a short course of antibiotics, but sometimes treatment is ineffective, or infections recur and become chronic. The tested treatment combined three bacteriophages (a virus that infects bacteria) with CRISPR-Cas3 to target the genomes of E. coli that cause about 95% of UTIs. CRISPR-Cas3 destroys the targeted DNA, which kills the bacteria. The treatment was delivered directly to the bladder by catheter in the phase 1 trial, which is the first CRISPR-based therapy to treat infection and the first to use Cas3, rather than Cas9. The trial results, announced in February, demonstrated safety and tolerability for the bacteriophage-CRISPR treatment. – Leigh MacMillan