The first two clinical trial participants to receive CRISPR-based treatments for inherited blood disorders have benefited from the experimental therapy and been symptom-free for several months, according to the companies that developed the treatment.
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The two patients, one with beta thalassemia and one with sickle cell disease, now have normalized hemoglobin levels, have not required blood transfusions, and have only experienced temporary and treatable side effects.
Although these benefits have only been seen for a relatively short time, the encouraging results suggest the patients have potentially been cured of their diseases, and that genome editing may one day provide a safe and long-lasting cure for these inherited blood disorders.
The two trials were jointly conducted by the companies Vertex Pharmaceuticals and CRISPR Therapeutics.
"A remarkable scientific and medical milestone"
This is the first clinical evidence to demonstrate that Crispr/Cas9 can be used to cure or potentially cure serious genetic illnesses. It's a remarkable scientific and medical milestone."
Jeffery Leiden, CEO of Vertex
Best known for its leading cystic fibrosis therapies, Vertex is most well-known for its leading cystic fibrosis therapies, but has more recently partnered with smaller companies such as CRISPR Therapeutics to develop a "toolbox of genetic therapies" for various inherited diseases, says Leiden.
Sickle cell disease and beta thalassemia
The CRISPR/Vertex treatment used to treat the two patients targets mutations in the hemoglobin gene that cause sickle cell disease and beta thalassemia.
In sickle cell, a mutation causes red blood cells to adopt an abnormal shape that prevents them from passing through blood vessels easily. This leads to organ damage, pain, and in many cases, premature death.
In beta thalassemia, a number of mutations result in reduced production of the molecule hemoglobin, which is needed to transport oxygen throughout the body. This leads to anemia and organ damage.
Reactivating fetal hemoglobin
Research has previously shown that both diseases may be cured if a form of hemoglobin called fetal hemoglobin, which the body stops producing soon after birth, can be reactivated.
The CRISPR/Vertex treatment, called CTX001, aims to do exactly that; it uses CRISPR to disable the genetic "brake" that halts the production of fetal hemoglobin, thereby providing the body with a new supply of the essential molecule.
In order to achieve this, hematopoietic (blood-producing) stem cells were isolated from the patients' bone marrow and gene-edited using CRISPR to fix the mutations that cause the diseases.
Once the patient undergoes busulfan treatment, which eliminates any mutation-carrying cells remaining in the bone marrow, the CRISPR-edited cells are infused back into the patient, and if all goes to plan, they head towards the bone marrow where they produce new, healthy, hemoglobin-packed red blood cells.
The gene-edited cells successfully engrafted in the bone marrow
The companies report that in both patients, the edited cells successfully engrafted in the bone marrow.
The patient with beta thalassemia, who used to require more than 16 blood transfusions every year, has not needed a transfusion since receiving the treatment. Nine months after undergoing the procedure, her total hemoglobin reached a near-normal level, which was boosted by a significant increase in fetal hemoglobin - a clear indication that CRISPR did what it was intended to.
Selim Corbacioglu (University of Regensburg, Germany) who treated the patient says freedom from transfusions promises to improve a patient's life dramatically: "You are fully dependent on your hospital as a chronic patient, you cannot go on long vacations. And you know that the complications of the chronic transfusions will hit you sooner or later."
The patient's most severe side effects, which were pneumonia, an enlarged liver, and low white blood cells count, were not unexpected, says Corbacioglu. They resulted from the busulfan conditioning regimen, but were temporary and have resolved with treatment: "These are typical complications" of wiping out bone marrow cells, he says… "There is absolutely no relation to the edited cells that were infused."
Since receiving her treatment in July, the patient with sickle cell disease has not suffered from any vaso-occlusive crisis (where sickled red blood cells become lodged in blood vessels). According to Haydar Frangoul of HCA Healthcare's Sarah Cannon Research Institute in Nashville, who treated the patient, she used to experience an average of seven crises per year and would require extended hospital stays three times a year:
"She was unable to attend to her family, unable to go watch her kids play football. It takes a lot of courage to become the first person in the world to receive an experimental treatment. It tells you how desperate she was."
Since receiving the CRISPR treatment, the patient's hemoglobin reached a normal level, of which nearly 50% was fetal hemoglobin. Experts think that a fetal hemoglobin level of 25% to 30% is enough to "cure" a sickle cell patient.
Frangoul's patient also suffered side effects, including gallstones and sepsis, but, again, this was attributed to the bone marrow preparation and not the CRISPR treatment itself.
"We can't help but think this brings a lot of promise"
CEO of CRISPR Therapeutics, Samarth Kulkarni, says that, despite the fact that these results have only been seen in two patients, it is encouraging.
The effect is so dramatic in these patients that we can't help but think this brings a lot of promise."
Samarth Kulkarni, CEO of CRISPR Therapeutics
Now that CRISPR and Vertex have the encouraging data in hand, they say additional sickle cell and beta thalassemia patients will soon be enrolled for the next phase of the trial. Ultimately, 45 patients will be treated with CTX001 soon and followed for two years.
Leiden says that while they do not yet have a timeline for when the treatment will be commercially available, "we want to get this to patients as soon as possible."