Vertex Pharmaceuticals and partner CRISPR Therapeutics have become the first US and European companies to move a CRISPR-based gene-editing product into the clinic, launching a trial of CTX001 in patients with β-thalassaemia.

Researchers first reported that CRISPR proteins could cut DNA in human cells in 2013, quickly raising hopes that these proteins might be harnessed as a new gene-editing modality. In the case of Vertex and CRISPR Therapeutics' CTX001 therapy, the technology is used to cut the DNA that encodes BCL11A, a transcription factor that typically represses production of fetal haemoglobin. In patients with β-thalassaemia, who carry mutations in the β-globin gene that compromise production of normal haemoglobin, CRISPR-induced disruption of BCL11A enables expression of compensatory fetal haemoglobin.

CTX001 is an autologous ex vivo therapy, in which haematopoietic stem and progenitor cells are harvested from patients, edited and then re-infused back into the patients. This type of strategy is typically considered to be less scientifically challenging than in vivo gene editing, because it side-steps drug delivery hurdles and reduces the risk of off-tissue editing.

The phase I/II trial will enroll 12 subjects in Europe. The FDA put the trial on clinical hold in the US before it started, “pending the resolution of certain questions”.

Other companies are also quickly advancing CRISPR products towards the clinic. Editas Medicine and Allergan plan to file later this year for approval to test EDIT-101, a CRISPR product that cuts out a mutation in CEP290, as an in vivo treatment for Leber congenital amaurosis. Intellia Therapeutics has partnered with Regeneron on an in vivo CRISPR product for the treatment of transthyretin amyloidosis, and with Novartis on an ex vivo product for sickle cell disease.

Sangamo Therapeutics, another gene-editing pioneer, has meanwhile advanced a few zinc-finger nuclease (ZFN)-based therapies into the clinic. In September it reported mixed data with its first in vivo gene-editing therapy. SB-913 places a normal functioning copy of the gene coding for iduronate 2-sulfatase (IDS) — under the control of the strong albumin promoter in the liver — in patients with the lysosomal storage disorder Hunter syndrome, which is caused by a lack of functional IDS. Treatment with SB-913 reduced disease-associated urinary glycosaminoglycan levels in two patients, but the company was unable to detect increased plasma levels of IDS. In March, the company also launched a phase I/II collaboration with Bioverativ, a Sanofi company, to test ST-400, a ZFN-based editor of BCL11A for the treatment of β-thalassaemia.