Gene-Editing Clinical Trials for Beta Thalassemia

Beta thalassemia belongs to a group of incurable genetic diseases known as the thalassemias, which are characterised by adult haemoglobin deficiency. Disinct from adult haemoglobin, foetal haemoglobin (HbF) is highly expressed and critical during foetal development, and is rapidly suppressed in most individuals early in life.

HbF has been the subject of decades of intense research and it is has become possible through genome engineering to switch its expression back on by interfering with its regulators. Reactivation of HbF expression has emerged as an attractive and popular strategy to treat the symptoms of beta thalassemia and related haemoglobinopathies by compensating for the lack of functional adult haemoglobin. You may read more about beta thalassemia and other genetic diseases of interest in our disease overview.

CTX001 - a CRISPR-edited blood stem cell therapy (Vertex Pharmaceuticals, Phase 1/2/3)

CTX001 is the most clinically-advanced gene-edited therapy for beta thalassemia and the related haemoglobinopathy sickle cell disease (SCD).

The new therapy is being developed by Vertex Pharmaceuticals as an autologous, ex vivo CRISPR-Cas9 gene-edited haematopoeitic stem and progenitor cell (HSPC) therapy, with trials ongoing for both for TDT and SCD (see here for a SCD clinical trial roundup).

CTX001 cells are genome-edited using CRISPR-Cas9 to make a small deletion in the BCL11A gene. BCL11A (or BAF Chromatin Remodeling Complex Subunit BCL11A) is a potent repressor of HbF expression and its disruption thus leads to reactivation of HbF in the edited cells.

CTX001 is being evaluated in the CLIMB-Thal-111 for TDT, and the most recent clinical data shared at the European Hematology Association Annual meeting in June 2021 was very promising.

Here, data was presented from 15 patients with TDT who had reached at least 3 months of follow up after CTX001 dosing and as such were suitable for assessment. These included six patients who have severe genotypes. All exhibited rapid and sustained increases in total and foetal haemoglobin, and all were transfusion-free at their most recent follow-up. At that time, five patients with TDT had reached follow-up times of more than one year, demonstrating a stable and durable response to CTX001 treatment. The safety data was consistent with autologous transplantation and conditioning treatment that is performed to make way for the gene-edited cells following transplantation.

ET-01 - a CRISPR-edited blood stem cell therapy (EdiGene, Phase 1)

Last autumn, EdiGene, a global biotechnology company with offices in China and Massachusetts, US, announced the first enrolment of a patient in its Phase 1 trial for ET-01 for transfusion-dependent beta thalassemia (TDT).

ET-01 is developed as an ex vivo autologous HSPC therapy that is gene-edited with CRISPR-Cas9 to express HbF.

Specifically, HbF is reactivated in ET-01 cells by disruption of the BCL11A-erythroid enhancer in patient-derived HSPCs. Besides its role in regulating HbF, BCL11A is also heavily involved in B lymphocyte maturation and haematopoeitic stem cell renewal. It was previously demonstrated that the erythroid enhancer present in the BCL11A gene sequence is required for BCL11A expression in erythroid but not in B-lymphoid cells. Therefore, specifically editing the BCL11A erythroid enhancer is anticipated to reactivate HbF while minimising any impact on BCL11A’s non-erythroid haematopoietic functions.

EdiGene plans to enrol 8 participants in the Phase 1 trial (age range 12 to 35 years), which will run over multiple sites in China. Primary outcome measures include safety and efficacy parameters, and the trial is expected to be complete in June 2024.

ST-400 - zinc finger nuclease-edited cell therapy (Sangamo Therapeutics, Phase 1/2)

ST-400 is an investigational autologous ex vivo cell therapy that consists of patient-derived gene-edited HSPCs. The cells are edited using Sangamo Therapeutics' zinc finger nuclease (ZFN) technology to disrupt a precise and specific sequence of the enhancer of the BCL11A gene. ST-400 is then infused back into the patient following conditioning chemotherapy.

ST-400 is currently being tested in the THALES study to assess its safety and tolerability in 6 adults with TDT between the age of 18 and 40 years of age. The primary objective is to understand the safety and tolerability of ST-400. Secondary objectives include assessments of HbF levels and transfusion requirements.

At the time of the American Hematology Society (ASH) Annual meeting in 2019, ST-400 had been manufactured for five patients (18-36 years of age), three of whom had been treated by that time. Preliminary data presented at that ASH meeting revealed haematopoietic reconstitution and on-target indels in circulating white blood cells in the three patients who had received ST-400.

In a company press release at that time, Angela Smith, MD, Associate Professor in the Division of Pediatric Blood and Marrow Transplantation at the University of Minnesota, who is also a Principal Investigator of the THALES study indicated that the full effects of the treatment may take as long as 12 to 18 months or more to manifest as is the case in other myeloablative conditioning studies of stem cell transplants for beta thalassemia patients. No further clinical data has been disclosed for ST-400.

ST-400 is being developed as part of a global collaboration between Sangamo Therapeutics and Sanofi, and with the support of a grant from the California Institute for Regenerative Medicine (CIRM). The expected study completion data is November 2022.

CRISPR-Cas9-mediated beta globin restoration in HSPCs (BioRay Labroatories, Phase 1/2)

BioRay Laboratories, a Shanghai-headquartered company specialised in gene and cell-based therapies are currently sponsoring two trials for CRISPR-edited cell therapies for beta thalassemia.

The first trial is a Phase 1/2 single-center, single-arm, open-label study to determine the safety and efficacy of β-globin-restored autologous HSPCs in beta thalassemia major patients with IVS-654 phenotype. The IVS-654 phenotype refers to a C→T substitution within the second intron of the HBB gene that was previously found to be one of the most common beta thalassaemia alleles affected in Chinese populations.

Donor-derived HSPCs will be CRISPR-Cas9-edited to restore β-globin expression. The exact gene-editing strategy has not been disclosed as of yet.

This study will take place in collaboration with PLA 923 Hospital in China and aims to enroll up to 12 child participants (5 to 15 years). The estimated study completion date is 1^st December 2023. Each participant will receive a single dose of edited cells throughout the year-long study.

BioRay is also sponsoring a Phase 1/2 trial for foetal haemoglobin-reactivated autologous HSPCs. This is a non-randomised, open label, single-site, single-dose, study in up to 12 child participants (5-15 years) with beta thalassemia major. The study will take place in partnership with the Xiangya Hospital of Central South University, China. The overall study aim is to evaluate the safety and efficacy of a single dose of autologous HSPCs that are edited with CRISPR-Cas9 to reactivate HbF expression. The HBG1 gene in donor-derived cells will be edited by CRISPR-Cas9 gene-editing cargo delivered via electroporation. The exact nature of the CRISPR editing strategy has not been disclosed.

The first participant was dosed in April 2020, and the estimated study completion date for the study, which is still recruiting, is June 2023.

Primary and secondary outcome measures are similar for both of BioRay's studies, and include safety and efficiency assessments at regular intervals to monitor haemoglobin levels and transfusion status. Subjects who enroll in either study will also be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment for up to 15 years post-transplant.

You can find all our previous news articles about gene-editing clinical trials here. For a complete overview of CRISPR IND approvals and ongoing gene-editing trials, check out CRISPR Medicine News' Clinical Trials Database.