First US Companies List a CRISPR Trial, for Blood Conditions

Ricki Lewis, PhD

September 07, 2018

CRISPR Therapeutics and Vertex Pharmaceuticals listed the first clinical trial for a treatment using CRISPR-Cas9 gene editing from US companies at on August 31. Participants will be adults with transfusion-dependent β-thalassemia, and the treatment will reactivate production of fetal hemoglobin.

The companies announced plans for the clinical trials of the product, CTX001, to treat both β-thalassemia and sickle cell disease (SCD), in December at the American Society of Hematology's annual meeting. In preclinical studies, CTX001 edited more than 90% of hematopoietic stem cells at the target site, leading to clinically relevant increases in fetal hemoglobin.

But on May 30, the US Food and Drug Administration (FDA) placed a clinical hold on the Investigational New Drug Application (IND) for the proposed phase 1/2 trial for SCD. The β-thalassemia trial will begin on 12 adults at a research site in Regensburg, Germany, with a goal of recruiting 45 patients. That is the trial listed at

The two companies "are currently working with the FDA to address the agency's questions regarding an IND to support the initiation of a phase 1/2 trial in sickle cell disease. We do not disclose our discussions with the FDA until we have an agreement on the plan forward," Heather Nichols, director of external communications at Vertex Pharmaceuticals, told Medscape Medical News.

However, clinical holds are not uncommon as a trial is attempting to get off the ground. The agency may request tweaks to the proposed protocol or analysis of findings, or further review preclinical findings.

Although registering at does not require regulatory approval, the new listing stands out among the current roster of 19 using search criterion "CRISPR." Of those, 10, from China, are using CRISPR to treat cancers. Trials from the University of Pennsylvania and the NIH Clinical Center also target cancer, and a trial from the Children's National Health System in Washington, DC, is for a diagnostic test. The other entries do not actually involve CRISPR.  

But one entry is relevant: A trial from the National Human Genome Research Institute seeks to assess opinions among people with SCD, their parents, and providers on the "integration of CRISPR in clinical care."

New Approach

The new approach behind CTX001 doesn't alter the mutant β globin gene behind both diseases, but instead switches on the fetal hemoglobin gene. To do so, CRISPR-Cas9 introduces small deletions into an "enhancer" gene called BCL11A in autologous hematopoietic stem and progenitor cells from patients, ex vivo.

BCL11A normally dampens fetal hemoglobin production shortly after birth, enabling β globin levels to build. The altered cells infused into patients give rise to erythroid progenitor cells that in turn give rise to erythrocytes containing fetal hemoglobin.

The fetal hemoglobin counters the sickling of SCD or compensates for the deficiency of β globin chains in β thalassemia. However, the approach doesn't work for people who do not produce any β globin (genotype βoβo).

"Our goal was to break the enhancer, rather than fix the hemoglobin mutation, but to do so in very precise ways that are only possible since gene editing technologies like CRISPR became available," Daniel Bauer, MD, PhD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Massachusetts, said in a 2015 Nature press release, when his team's demonstration of the proof-of-principle in human erythroid progenitor cells was published in the journal.

Reawakening the fetal hemoglobin gene to treat SCD isn't a new idea. The field started in the 1960s with the observation that people with hereditary persistence of fetal hemoglobin (HPFH) have normal blood oxygenation.

Investigation of hydroxyurea to recapitulate the HPFH phenotype began in 1982, with FDA approval of the drug to treat SCD in adults in 1998 and in children in 2017. Hydroxyurea, taken orally daily, reduces the frequency of painful crises and the need for blood transfusions. The CRISPR-based approach would provide a possible one-time treatment.

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