临床进展 | 中国首次基因编辑治愈外籍患者

此次接受正序生物碱基编辑治疗的老挝患者为输血依赖型β-地贫患者，在接受CS-101治疗前，输血频率达到每月2单位红细胞。患者在接受CS-101治疗后两个月内，总血红蛋白浓度升高至120 g/L以上并且保持稳定，成功实现脱离输血依赖的目标。

截至目前，这项由正序生物与广西医科大学第一附属医院共同合作开展的针对重型β-地中海贫血症的临床研究中，已有多名β-地中海贫血患者顺利接受CS-101治疗，并均已成功摆脱输血依赖。正序生物CS-101注射液也在今年4月获得NMPA的IND批准，正式启动了临床I期试验。

正序生物CS-101临床研究的顺利开展，得益于该疗法所用基因编辑技术的安全性和靶点的有效性。正序生物CS-101疗法的原理，是通过采集患者自体造血干细胞，利用上海科技大学自主研发的高精准变形式碱基编辑器tBE（transformer Base Editor）（Wang et al., Nat Cell Biol, 2021），对患者自体造血干细胞中的HBG1/2启动子区域进行精准碱基编辑，模拟健康人群中天然存在的有益碱基突变，重新激活γ-珠蛋白的表达，重建血红蛋白的携氧功能（Han et al., Cell Stem Cell, 2023）。进一步，将编辑后的造血干细胞回输至患者体内，使得患者自身血红蛋白浓度达到健康人水平，从而彻底摆脱输血依赖。

相较于传统的输血疗法和异体造血干细胞移植法，正序生物CS-101注射液来自于患者的自体干细胞，制备周期短，患者不需要长时间等待，只需要数周即可实现“一次治疗，终身治愈”的效果；相较于其他基于CRISPR技术的β-地贫基因编辑疗法，正序生物CS-101注射液具有更好的有效性和安全性，采用的tBE技术不会造成DNA双链断裂，有效避免了DNA大片段缺失、染色体异位、脱靶突变等风险，同时所编辑的靶点可更高效地激活胎儿血红蛋白表达，使患者迅速完成造血重建，更快地达到健康人血红蛋白水平，更早摆脱输血依赖。

正序生物CS-101注射液可以更安全、快速、有效的彻底治愈β-血红蛋白病，将为全球β-血红蛋白病患者带来福音。血红蛋白病是全世界最普遍的单基因遗传病，其中，β-地中海贫血症是一种流行于我国南方地区的遗传性血红蛋白病，在地中海沿岸国家、南亚和东南亚各国也较为多见。据统计，我国地中海贫血症突变基因携带者约有3000万人，其中，重型和中间型地贫患者约为30万人；东南亚地区地中海贫血症突变基因携带者约有3亿人，占总人口的44.60%；另一种常见的遗传性血红蛋白病是镰刀型贫血症，在全球多个国家也广泛存在，全球镰刀型贫血症突变基因携带者约占总人口的3.5%，每年大约有30万名婴儿出生时患有镰刀型贫血症。

目前，正序生物CS-101注射液针对β-地中海贫血症的临床I期试验正在稳步推进。同步，关于CS-101 注射液治疗镰刀型贫血症的临床试验也正在筹备中，针对镰刀型贫血症患者的全球招募计划已经启动（详情请联系CT@correctsequence.com）。

（特别感谢广西医科大学第一附属医院、上海科技大学及上海临床研究中心）

广西医科大学第一附属医院：

基因编辑治愈首位外籍患者，老挝18岁地贫女孩获新生

The First Clinical Gene Editing Therapy to Treat An Overseas Patient in China

CorrectSequence Therapeutics’ CS-101 Cures One Laos Patient with β-Thalassemia

On July 20, 2024, Shanghai, China, CorrectSequence Therapeutics Co., Ltd. (Correctseq) announced a significant milestone in their base editing therapy CS-101 for transfusion-dependent β-thalassemia. Utilizing their pioneering transformer Base Editor (tBE), Correctseq has successfully cured the first overseas patient with transfusion-dependent β-thalassemia in a clinical trial in collaboration with the First Affiliated Hospital of Guangxi Medical University. The patient has achieved a sustained transfusion-free status for over two months, with the hemoglobin level stabilized at above 120 g/L. As a result, the patient has been able to resume a normal life. (The First Affiliated Hospital of Guangxi Medical University: 基因编辑治愈首位外籍患者，老挝18岁地贫女孩获新生 The First Overseas Patient Cured by the Gene Editing Therapy, An 18-Year-Old Girl with β-Thalassemia from Laos is Given A New Life)

The first overseas patient who received CS-101 treatment is from Laos. The patient was diagnosed with transfusion-dependent β-thalassemia and required 2 units of red blood cells (RBC) per month prior to receiving CS-101 treatment. Following the therapy, the patient’s hemoglobin level has reached at above 120 g/L within two months after treatment and maintained at such level as of the report date. As a result, the patient successfully achieved independent of blood transfusions.

In April 2024, CS-101 received IND (Investigational New Drug) approval from the National Medical Products Administration (NMPA) of China. This approval has allowed the Phase I clinical trial to commence, marking a significant milestone in the development of CS-101 as a promising treatment for transfusion-dependent β-thalassemia.

The successful implementation of the CS-101 clinical trial is a testament to the safety of the base editing technology employed and the selection of effective targets. The underlying principle of CS-101 involves the collection of the patient's own hematopoietic stem cells, followed by the utilization of tBE. Pioneered by scientists at ShanghaiTech University (Wang et al., Nat Cell Biol, 2021), this technology enables the precise editing of the DNA sequence within the promoter region of the gene responsible for encoding γ-globin (HBG1/2).

By mimicking a naturally occurring beneficial single-nucleotide variant found in individuals with hereditary persistence of fetal hemoglobin, the tBE reactivates γ-globin expression, resulting in the production of functional HbF (Han et al., Cell Stem Cell, 2023). The edited stem cells are then reintroduced into the patient's body, enabling continuous production of blood cells with functional hemoglobin. This approach eliminates the need for frequent blood transfusions, offering a significant advancement in the treatment of transfusion-dependent β-thalassemia.

Compared to traditional blood transfusion therapy and allogeneic hematopoietic stem cell transplantation, CS-101 offers several compelling advantages. One of the key benefits is its short preparation period. Another is eliminating the need for long waiting time for a matching donor since it utilizes the patient’s own hematopoietic stem cells. CS-101 has the potential to achieve a "single treatment, lifetime cure" within a few weeks.

In comparison to other CRISPR-based β-thalassemia gene editing therapies, CS-101 does not carry safety risks associated with large DNA fragment deletions, chromosomal translocation, or off-target mutations. This enhances the overall safety profile of the treatment and reduces potential complications.

Overall, CS-101 offers a promising approach for the treatment of transfusion-dependent β-thalassemia, providing faster and safer hematopoietic reconstruction, quicker restoration of hemoglobin levels, and a shorter path to achieving transfusion independence compared to other therapies.

CS-101 offers a potential complete cure for β-hemoglobinopathy in a safer, faster, and more efficient manner, instilling new hope for patients worldwide. Hemoglobinopathies encompass the most prevalent group of monogenic diseases globally. Among them, β-thalassemia is particularly prevalent in southern China, as well as in Mediterranean countries, South Asian and Southeast Asian countries. In China alone, there are approximately 30 million individuals carrying the thalassemia mutant gene, with around 300,000 severe and intermediate thalassemia patients. In Southeast Asia, approximately 300 million people carry the thalassemia mutant gene, accounting for 44.60% of the total population in the region.

Another common genetic hemoglobinopathy is sickle cell disease (SCD), which is prevalent in various countries worldwide. Approximately 3.5% of the global population carries the mutant gene for SCD, and around 300,000 newborns worldwide are affected by SCD each year.

The Phase I clinical trial for the treatment of β-thalassemia with CS-101 is proceeding steadily. In tandem, a clinical trial targeting SCD with CS-101 are in active preparation, which is an important step towards addressing the needs of SCD patients. A global recruitment program for SCD patients is recently launched, underscoring Correctseq’s commitment in providing care and resolution for patients worldwide.

Correctseq is dedicated to expediting the clinical translation of pioneering gene editing technologies. By developing best-in-class gene editing therapy and first-in-class base editing therapy, Correctseq aims to provide safe, reliable, and cost-effective treatment options for patients worldwide.

For more detailed information about the clinical trials and recruitment program, it is recommended to contact CT@correctsequence.com.

Acknowledgements: The First Affiliated Hospital of Guangxi Medical University, ShanghaiTech University, Shanghai Clinical Research and Trial Center.

The First Affiliated Hospital of Guangxi Medical University: 

基因编辑治愈首位外籍患者，老挝18岁地贫女孩获新生

The First Overseas Patient Cured by the Gene Editing Therapy, An 18-Year-Old Girl with β-Thalassemia from Laos is Given A New Life

About CorrectSequence Therapeutics

CorrectSequence Therapeutics^TM (Correctseq^TM), is a clinical-stage biotech company employing its proprietary transformer Base Editor (tBE) to pioneer next-generation gene editing therapies. Our leading pipeline candidate, CS-101, utilizing innovative base editor targeting HBG, curing β-hemoglobinopathies, has obtained IND approval from the China NMPA. Clinical data demonstrate its superior performance. Proof-of-concept (POC) data in mice for in vivo pipelines using tBE-editing therapies via lipid nanoparticle (LNP) delivery are available, including targets for hereditary angioedema (HAE), hypercholesterolemia, and hypertriglyceridemia. Ex vivo multiplex editing of T cells on multiple targets simultaneously preserved T cell growth and function in vivo compared to non-edited cells, establishing tBE as the ideal gene editing tool for the next-generation cell therapy development. We are developing multiple pipelines targeting genetic diseases, cancer immunotherapy, metabolic disorders, and cardiovascular diseases.

Please refer to our homepage for more information about the tBE and its therapeutics applications at www.correctsequence.com