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Therapeutic Relevant Gene Editing

In a paper published in the July 31, 2019 issue of Science Translational Medicine, researchers at Fred Hutchinson Cancer Research Center used CRISPR-Cas9 to edit long-lived blood stem cells to reverse the clinical symptoms observed with several blood disorders, including sickle cell disease and beta-thalassemia.

It’s the first time that scientists have specifically edited the genetic makeup of a specialized subset of adult blood stem cells that are the source of all cells in the blood and immune system.

The proof-of-principle study suggests that efficient modification of targeted stem cells could reduce the costs of gene-editing treatments for blood disorders and other diseases while decreasing the risks of unwanted effects that can occur with a less discriminating approach.

Targeting this portion of stem cells could potentially help millions of people with blood diseases,” said Kiem, who holds the Stephanus Family Endowed Chair for Cell and Gene Therapy.

For this preclinical study, which is expected to lead to human trials, the researchers picked a gene related to sickle cell disease and beta-thalassemia, which are caused by a genetic defect in how haemoglobin is made. Other studies have shown that symptoms are reversed by reactivating a version of haemoglobin that works during fetal development but is then turned off by our first birthdays.

The Fred Hutch researchers used CRISPR-Cas9 gene editing to a remove a piece of genetic code that normally turns off fetal haemoglobin proteins. Snipping this control DNA with CRISPR enables red blood cells to continuously produce elevated levels of fetal haemoglobin.

The edits were taken up efficiently by the targeted cells: 78% took up the edits in the lab dish before they were infused. Once infused, the edited cells settled in (“engrafted”), multiplied and produced blood cells, 30% of which contained the edits. This resulted in up to 20% of red blood cells with fetal haemoglobin, the type of haemoglobin that reverses disease symptoms in sickle cell disease and thalassemia.

“Not only were we able to edit the cells efficiently, we also showed that they engraft efficiently at high levels, and this gives us great hope that we can translate this into an effective therapy for people,” Kiem said. “Twenty percent of red blood cells with fetal haemoglobin — what we saw with this method — would be close to a level sufficient to reverse symptoms of sickle cell disease.”

The scientists also believe that carrying out genetic fixes on the smaller pool of cells required for therapeutic benefit will lessen safety concerns and reduce the risk of off-target effects.

“Since the CRISPR technology is still in early stages of development, it was important to demonstrate that our approach is safe. We found no harmful off-target mutations in edited cells and we are currently conducting long-term follow-up studies to verify the absence of any undesired effect,” said first author Dr. Olivier Humbert, a staff scientist in the Kiem Lab.

This was the first study to specifically edit a small population of blood cells that Kiem’s team identified in 2017 as solely responsible for regrowing the entire blood and immune system. His team distinguished this select group as CD90 cells, named for a protein marker that sets them apart from the rest of the blood stem cells (known by another protein marker, CD34).

The self-renewing properties of this population of stem cells make them a powerful potential candidate to deliver gene therapy because they can provide long-term production of these genetically modified blood cells and thus could cure a disease for an entire lifetime. Since they represent a mere 5% of all blood stem cells, targeting them with gene-editing machinery would require fewer supplies and potentially be less costly.

FDA Approval of Adakveo

The FDA approved Nov. 15 Novartis’ drug, Adakveo, the first targeted therapy approved to treat sickle cell disease.

Adakveo is designed to reduce the frequency of vaso-occlusive crisis, a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells.

The clinical trial showed patients treated with Adakveo had a median annual rate of 1.63 healthcare visits for vaso-occlusive crisis, compared to an annual rate of 2.98 visits for patients on a placebo. Additionally, 36 percent of patients did not experience vaso-occlusive crisis during the study, and it delayed the time patients’ first experienced vaso-occlusive crisis after starting treatment from 1.4 months to 4.1 months.

Common side effects of Adakveo include back pain, nausea, fever and joint pain. Physicians are advised to monitor patients being treated with Adakveo for infusion-related reactions and to discontinue for severe reactions. Patients should also be monitored for interference with automated platelet counts or platelet clumping.

Adakveo is designed for patients 16 years and older.

The treatment was given priority review, breakthrough therapy designation and orphan drug designation.


Voxelotor, a potential treatment for sickle cell anemia (SCA), has been given breakthrough therapy designation (BTD), Global Blood Therapeutics (GBT) recently announced.

Voxelotor (previously called GBT440) is a potential once-daily oral medicine for SCA patients. It was designed to increase haemoglobin’s binding of oxygen, which keeps red blood cells in their normal round shape, and helps prevent cells’ clumping and sickling.

GBT believes that the ability to repair haemoglobin function and improve oxygen delivery makes voxelotor a potential disease-modifying therapy in SCA. The medicine previously was granted fast track, orphan drug (given to promising products for the diagnosis and/or treatment of rare diseases) and rare paediatric disease designations.

The U.S. Food and Drug Administration (FDA) grants BTD to therapies for serious or life-threatening diseases if they show substantial improvement over existing medications in preliminary clinical results. The BTD label accelerates development and review of the new treatment.

The clinical data backing up volexotor’s potential was obtained from multiple studies. The ongoing multi-center Phase 3 HOPE study (NCT03036813) in SCA patients 12 to 65 years’ old showed positive efficacy and safety data. The study is still recruiting patients.

BTD also was based in results from a Phase 1 trial (NCT02285088) and its Phase 2 extension in adults (NCT03041909), and in the ongoing Phase 2 HOPE-KIDS 1 study (NCT02850406) in children 6 to 17 years old. This study is being conducted in the U.S. and also is recruiting patients.

The European Medicines Agency had granted volexotor Priority Medicines (PRIME) designation to treat SCA. This is a mechanism to speed up development of medicines that target unmet medical needs.