Scalable Manufacturing and Preclinical Safety and Efficacy Data of ET-01, a CRISPR/Cas9-Edited Autologous CD34+ Hematopoietic Stem Cell Therapy Targeting BCL11A Erythroid Enhancer for Transfusion-Dependent β-Thalassemia

Recently, Edigene disclosed that the company will present initial data from its beta-thalassemia gene therapy program (ET-01) for the first time at the 61st American Society of Hematology (ASH) Annual Meeting, held from December 7 to 10, 2019. Edigene is an innovative biopharmaceutical company dedicated to developing novel therapies for diseases that are difficult to treat with conventional approaches, leveraging genome editing technologies, and providing more innovative solutions for new drug development.

β-thalassemia is a group of hemoglobinopathies characterized by partial or complete suppression of β-globin chain synthesis, with onset typically occurring in infancy. It is a severe, chronic, progressive anemia; the earlier the onset, the more severe the disease, and symptoms become increasingly apparent with age. Without intervention, most patients with severe forms do not survive beyond five years of age.

Currently, the standard clinical care involves regular red blood cell transfusions and iron chelation therapy, a approach that may lead to iron overload and subsequent organ damage. The only curative treatment is allogeneic hematopoietic stem cell transplantation; however, this option is limited to a small subset of young patients who have an HLA-matched donor.

Epidemiological data indicate that elevated fetal hemoglobin (HbF) levels can ameliorate clinical symptoms in some patients with β-thalassemia. Given the characteristics of the disease, β-thalassemia has become a focal point for gene therapy research. BCL11A is a critical transcription factor that plays a key role in suppressing γ-globin expression. ET-01, currently under development by BoYa JiYin, utilizes CRISPR/Cas9 to edit patients’ autologous hematopoietic stem cells, disrupting the erythroid enhancer of BCL11A and activating γ-globin expression to achieve therapeutic effects for β-thalassemia.

Abroad, Sangamo (ZFN gene editing) and CRISPR Therapeutics (founded by Emmanuelle Charpentier) have both advanced their thalassemia treatment research programs into the clinical trial stage. Meanwhile, research based on CRISPR-edited hematopoietic stem cell therapy has also gained recognition in China:

Supported by the National Major Science and Technology Project for Infectious Diseases, Professor Deng Hongkui from the School of Life Sciences at Peking University, Professor Chen Hu from the 307th Hospital, and Professor Wu Hao from Beijing Youan Hospital published an article titled “CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia” in The New England Journal of Medicine on September 11. The article reports the first case in which the CCR5 gene was edited in hematopoietic stem and progenitor cells (HSPCs) using CRISPR-Cas9 gene-editing technology and successfully transplanted into a patient suffering from both HIV and acute lymphocytic leukemia. Data showed that the transplantation therapy achieved complete remission of the patient’s acute lymphocytic leukemia. Donor cells carrying the CCR5 mutation survived in the recipient’s body for up to 19 months without significant post-editing adverse effects, thereby preliminarily exploring the feasibility and safety of this approach.

This study rapidly translated basic research into Phase I clinical trials without raising ethical concerns, holding significant implications for advancing the global clinical application of CRISPR-based gene editing therapies.

Research data from Edigene indicate that the BCL11A enhancer can be edited with high precision and efficiency in ET-01, leading to elevated HbF levels. Currently, Edigene has established a cGMP-compliant manufacturing facility and achieved clinical-scale expanded production.

This presentation will highlight the clinical-grade scaled manufacturing of ET-01, as well as the safety and efficacy data from in vitro and in vivo preclinical studies supporting its subsequent clinical trials. These data demonstrate that CRISPR/Cas9 efficiently and precisely modifies specific DNA targets in donor-derived autologous CD34+ hematopoietic stem cells within ET-01, leading to a significant increase in fetal hemoglobin levels in erythrocytes differentiated in vitro, along with a favorable safety profile in preclinical studies.

“In China, there are as many as 30 million carriers of the thalassemia gene, with 50,000 cases of severe thalassemia alone. Compared with Western countries, these patients have a much shorter life expectancy, with the vast majority not surviving beyond the age of 20, imposing immense psychological distress and financial hardship on their families,” said Dr. Wei Dong, CEO of EditoGene. “We are encouraged by the research progress achieved in the ET-01 program. We plan to engage with Chinese regulatory authorities in the near term, aiming to advance this technology into clinical trials as soon as possible to provide potential new treatment options for patients in China with severe β-thalassemia who are in urgent need.”

EdiGene, Inc. is an innovative biopharmaceutical company dedicated to developing novel therapeutic solutions based on genome editing technologies for diseases that are difficult to treat with conventional therapies, including intractable genetic disorders and cancers, thereby addressing urgent unmet medical needs. Additionally, it provides innovative solutions for drug discovery through high-throughput genome editing screening technologies.

Founded in 2015, Edita Genomics is headquartered in Beijing, with subsidiaries in Guangzhou and Cambridge, USA.