CRISPR, the technology first developed by Jennifer Doudna and colleagues at the University of California – Berkeley, is taking on the job of curing hereditary diseases here in the third decade of the 21st century. This is an exciting medical development that has profound implications for some of the most challenging genetic-caused conditions whether in humans or other species.
CRISPR today is being tested in clinical trials to treat Type-1 Diabetes Mellitus, Glycogen Storage Disease, Duchenne Muscular Dystrophy, Myotonic Dystrophy, Cystic Fibrosis, and a number of refractory cancers including blood disorders and carcinomas. Add to this sickle cell anemia.
What do we know about this disease?
Today it is the most commonly inherited blood disease in the United States affecting mostly African Americans. About one in 12 carries the genetic trait, a mutation of the hemoglobin-Beta gene located on chromosome 11. That mutation causes red blood cells to deform from being circular to sickle-shaped. This makes the blood cells stiff and sticky causing clotting, organ and tissue damage. When the immune system encounters sickle-shaped blood cells they are destroyed. Hence those suffering from the genetic defect become anemic and suffer chest pains, strokes, and damage to the spleen, kidneys, and liver. They are highly vulnerable to bacterial infections.
The inherited genetic defect can be passed from parent to child. If both parents have the defect, their baby has a one in four chance of being born with the disease. If only one parent has the defect, the baby has a one in two chance of inheriting the trait and passing it along to their future children.
Using CRISPR to repair the mutation seems like a natural for the technology. And now the U.S. Food and Drug Administration has approved a clinical trial using the tool for that purpose. The planned trial is to last four years and is being led by physicians from the University of California – San Franciscio (UCSF) and University of California – Los Angeles (UCLA). The first site is the Benioff Children’s Hospital in Oakland. The Los Angeles site is the Broad Stem Cell Research Center associated with UCLA. Six adults, and three adolescents with severe sickle cell disease are the initial enrollees for the trial which will use CRISPR to snip out the defective beta-globin gene in these patients and replace them with a repaired version. If successful it will produce a cure and become a preventative so that no one need experience the irreversible complications that impact sickle cell anemia sufferers.
The trial will use each of the participants’ own hematopoietic stem cells harvested from bone marrow. These will be removed and then gene-edited and cultured. The remaining bone marrow of each participant will then be destroyed using chemotherapy. The gene-edited cells will then be reinfused into the bone marrow where they will multiply. The trial will mark its success if the genome-edited stem cells correct the mutation enough to impact the red blood cell population. A correction in 20% of the bone marrow should be sufficient to knock out the participants’ sickle cells.
In future, the hope is to create a technique for correcting the sickle cell mutation without removing the stem cells or destroying bone marrow because this would shorten the amount of time the participants are immune-compromised and subject to the potential complications that come with the use of strong chemotherapy drugs. This could be accomplished using a nanoparticle delivery of the CRISPR enzyme directly to the stem cells.
If the current four-year trial is successful it will open the door to treating all types of blood disorders using a similar modality. And ultimately if the treatment can be delivered directly to stem cells within the body, it will be revolutionary.