Beam Therapeutics 宣布临床前数据，突出显示碱基编辑器针对慢

StephenW

Beam Therapeutics 宣布临床前数据，突出显示碱基编辑器针对慢性乙型肝炎感染疾病驱动因素的潜力

光束疗法
2021 年 9 月 27 日，星期一，晚上 8:30·6 分钟阅读
在本文中：

将在 2021 年国际 HBV 会议口头报告期间提交的数据

马萨诸塞州剑桥市，2021 年 9 月 27 日（全球新闻通讯社）——通过碱基编辑开发精准基因药物的生物技术公司 Beam Therapeutics Inc.（纳斯达克股票代码：BEAM）今天公布了临床前数据，证明了 Beam 胞嘧啶碱基编辑器的潜力（ CBEs) 以减少病毒标志物，包括乙型肝炎表面抗原 (HBsAg) 的表达，并在体外模型中防止乙型肝炎病毒 (HBV) 的病毒反弹。这些数据将于今天（2021 年 9 月 27 日）与里昂 INSERM 癌症研究中心的 Fabien Zoulim 实验室合作，在 2021 年国际 HBV 会议上进行题为“使用胞嘧啶碱基编辑器的 cccDNA 灭活”的口头报告中公布。

HBV 会导致严重的肝脏感染，并可能成为慢性感染，从而增加出现肝硬化、肝功能衰竭或肝癌等危及生命的健康问题的风险。慢性 HBV 感染的特征是共价闭合环状 DNA (cccDNA) 的持续存在，这是一种独特的 DNA 结构，在肝细胞核中响应 HBV 感染而形成。此外，HBV DNA 整合到人类基因组中，成为 HBsAg 的来源。虽然目前可用的治疗方法可以控制 HBV 复制，但它们不能从受感染的肝细胞中清除 cccDNA。这种无法防止 HBV 感染从 cccDNA 反弹是治愈 HBV 的关键挑战。

碱基编辑器旨在将特定 DNA 碱基直接和不可逆地转化为另一个碱基，而不会引起双链断裂。在 HBV 感染的细胞中，CBE 可以在多个位置靶向 cccDNA 微染色体，在病毒基因组中引入精确且永久的终止密码子，旨在使病毒基因沉默而没有染色体重排的风险。

“乙型肝炎是一场重大的全球健康危机，目前全世界有超过 2.5 亿人被诊断患有慢性病。 Beam 总裁兼首席科学官 Giuseppe Ciaramella 博士说：“尽管目前有治疗方法，但寻找慢性 HBV 治愈方法的一个关键挑战是能够防止 cccDNA 引起的感染反弹。” “今天提供的数据表明，使用我们的新型 CBE，我们可以直接靶向和沉默 cccDNA 以显着减少相关的 HBV 病毒复制子，而无需从细胞中清除 cccDNA。此外，由于 HBV 序列广泛整合到受感染细胞的基因组中，多重碱基编辑器非常适合永久沉默 HBV 遗传元件，而不会产生双链断裂或遗传重排。这些数据强调了我们相信碱基编辑在治疗 HBV 感染患者以及广泛的严重遗传疾病方面可以提供的优势。”

今天公布的结果来自一项临床前体外研究，旨在评估碱基编辑为慢性乙型肝炎疾病提供新型治疗的潜力。在这项研究中，受感染的人类肝癌 HepG2-NTCP 细胞（易受 HBV 感染）和长期原代人类肝细胞共培养物使用选定的靶向 HBV 的 gRNA 和编码 mRNA 的 CBE 进行多重编辑。编辑包括引入终止密码子以减少 HBsAg 和 HBeAg，并使 HBV 基因和 cccDNA 沉默。数据发现表明：

    将设计用于引入终止密码子的两个 gRNA 进行多路复用，导致相关 HBV 病毒标记物（HBsAg、HBeAg、HBV DNA、3.5kb RNA）大量同时减少

    双 gRNA cccDNA 靶向 CBE 使 cccDNA 的编辑效率提高了 30%-60%，而不会降低 cccDNA 水平；

    碱基编辑试剂与标准抗病毒药物拉米夫定的组合处理使碱基编辑效率提高了 20%，从而实现了高抗病毒功效；和

    碱基编辑可防止长期感染的原代肝细胞中的 HBV 反弹。

这些结果表明，CBE 可以在 cccDNA 中引入永久性突变，并在相关体外模型中防止 HBV 反弹。基于这些发现，Beam 计划在相关的体内概念模型验证中评估其基础编辑方法。

关于光束疗法

Beam Therapeutics（纳斯达克股票代码：BEAM）是一家生物技术公司，致力于建立领先的、完全集成的精准基因药物平台。 为了实现这一愿景，Beam 组装了一个平台，其中包括一套基因编辑和传递技术，并且正在构建内部制造能力。 Beam 的基因编辑技术套件以碱基编辑为基础，这是一种专有技术，可在目标基因组序列上实现精确、可预测和高效的单碱基变化，而不会在 DNA 中造成双链断裂。 这使得 Beam 正在使用各种潜在的治疗性编辑策略来推进多元化的基础编辑程序组合。 Beam 是一家以价值观为导向的组织，致力于为员工、尖端科学以及为患有严重疾病的患者提供终身治疗的愿景。

StephenW

Beam Therapeutics Announces Preclinical Data Highlighting Potential of Base Editors to Target Disease Drivers of Chronic Hepatitis B Infection

Beam Therapeutics
Mon, September 27, 2021, 8:30 PM·6 min read
In this article:

Data to be Presented During an Oral Presentation at the 2021 International HBV Meeting

CAMBRIDGE, Mass., Sept. 27, 2021 (GLOBE NEWSWIRE) -- Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, today announced preclinical data demonstrating the potential of Beam’s cytosine base editors (CBEs) to reduce viral markers, including hepatitis B surface antigen (HBsAg) expression, and prevent viral rebound of hepatitis B virus (HBV) in in vitro models. These data will be presented today, September 27, 2021, in partnership with Fabien Zoulim’s laboratory at the INSERM Cancer Research Center of Lyon, during an oral presentation titled, “cccDNA Inactivation Using Cytosine Base Editors,” at the 2021 International HBV Meeting.

HBV causes serious liver infection that can become chronic, increasing the risk of developing life-threatening health issues like cirrhosis, liver failure or liver cancer. Chronic HBV infection is characterized by the persistence of covalently closed circular DNA (cccDNA), a unique DNA structure that forms in response to HBV infection in the nuclei of liver cells. Additionally, the HBV DNA integrates into the human genome becoming a source of HBsAg. While currently available treatments can manage HBV replication, they do not clear cccDNA from the infected liver cells. This inability to prevent HBV infection rebound from cccDNA is a key challenge to curing HBV.

Base editors are designed to enable direct and irreversible conversion of a specific DNA base into another without inducing double-stranded breaks. In HBV infected cells, CBEs can target the cccDNA minichromosome at multiple locations, introducing precise and permanent stop codons in the viral genome, which are intended to silence the viral genes without the risk of the chromosomal rearrangements.

“Hepatitis B is a major global health crisis, with more than 250 million people currently diagnosed with chronic disease worldwide. Despite current therapeutic approaches, a key challenge to finding a curative treatment to chronic HBV is being able to prevent infection rebound from cccDNA,” said Giuseppe Ciaramella, Ph.D., president and chief scientific officer of Beam. “The data being presented today show that using our novel CBE, we can directly target and silence cccDNA to significantly reduce relevant HBV viral replicators, without the need to clear cccDNA from the cell. Furthermore, because HBV sequences are extensively integrated in the genome of infected cells, multiplex base editors are a natural fit for permanently silencing HBV genetic elements without creating double-stranded breaks or genetic rearrangements. These data underscore the advantages we believe base editing can offer in treating patients with HBV infection as well as a wide range of serious genetic diseases.”

The results announced today are from a preclinical in vitro study designed to evaluate the potential of base editing to provide a new type of treatment for chronic hepatitis B disease. In the study, infected human hepatoma HepG2-NTCP cells, which are susceptible to HBV infection, and long-term primary human hepatocyte co-cultures, were multiplex edited with selected HBV-targeting gRNAs and mRNA-encoding CBEs. Edits included the introduction of stop codons to reduce HBsAg and HBeAg and silence the HBV gene and the cccDNA. Data findings show that:

    Multiplexing two gRNAs designed to introduce stop codons led to substantial, simultaneous reduction of relevant HBV viral markers (HBsAg, HBeAg, HBV DNA, 3.5kb RNA)

    Dual gRNA cccDNA-targeting CBE led to 30%-60% editing efficiency of the cccDNA, without reducing cccDNA levels;

    Combinatorial treatment of the base editing reagents with standard antiviral lamivudine resulted in 20% higher base editing efficiency leading to high antiviral efficacy; and

    Base editing prevented HBV rebound in long-term infected primary hepatocytes.

These results indicate that CBEs can introduce permanent mutations in cccDNA and prevent HBV rebound in relevant in vitro models. Based on these findings, Beam plans to evaluate its base editing approach in relevant in vivo proof of concept models.
About Beam Therapeutics

Beam Therapeutics (Nasdaq: BEAM) is a biotechnology company committed to establishing the leading, fully integrated platform for precision genetic medicines. To achieve this vision, Beam has assembled a platform that includes a suite of gene editing and delivery technologies and is in the process of building internal manufacturing capabilities. Beam’s suite of gene editing technologies is anchored by base editing, a proprietary technology that enables precise, predictable and efficient single base changes, at targeted genomic sequences, without making double-stranded breaks in the DNA. This enables a wide range of potential therapeutic editing strategies that Beam is using to advance a diversified portfolio of base editing programs. Beam is a values-driven organization committed to its people, cutting-edge science, and a vision of providing life-long cures to patients suffering from serious diseases.