Salmonella typhimurium-based Bacteriotherapy for Orphan Benign Tumors: Neurofibromatosis Type II (NF2)

基于鼠伤寒沙门氏菌的孤儿良性肿瘤细菌疗法:II 型神经纤维瘤病 (NF2)

基本信息

  • 批准号:
    10267742
  • 负责人:
  • 金额:
    $ 19.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-30 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

Neurofibromatosis type 2 (NF2) is a rare genetic disorder that affects about 1 in 25,000 individuals globally. While usually benign, these tumors result in severe morbidity and mortality in affected individuals. Almost all NF2 patients lose their hearing, and many lose the ability to walk and even to see. NF2 patients’ average age at death is 36 years, many of whom die in adolescence or early adulthood from their disease. NF2 is an orphan indication and represents a major unmet medical need, thus supporting an FDA Fast Track designation. NF Bio estimates the NF2 commercial opportunity to exceed US$1B in annual peak year sales. Success in NF2 treatment will also lead to testing in other benign and schwannoma-related neoplasms such as NF1. Operative resection and radiotherapy are the current standards of care. However, these treatments have major limitations. Resection can lead to a significant sensory loss including deafness, pain, facial paralysis, and motor dysfunction. Resection also is not always possible due to the risk of nerve or brain stem damage. Radiotherapy can be contraindicated due to the risk of malignant transformation and typically does not eliminate the schwannoma. Affected individuals typically have multiple schwannomas with tumors arising throughout life, further increasing disease-associated suffering and limiting the utility of surgical resection. There is no approved pharmaceutical therapy and a limited clinical trial pipeline. NF Bio has developed an NF2 bacteriotherapy that utilizes intra-tumoral (i.t.) injection of attenuated S. typhimurium, delivered in an image-guided fashion (MRI or ultrasound) by neurosurgeons, otolaryngologists, pain medicine physicians, or interventional radiologists Use of this bacterial therapy for schwannomas is justified by the fact that Salmonella thrives in the hypoxic areas of highly vascularized tissues, which is a hallmark of NF2 schwannomas, and its anti-tumor cytotoxic mechanisms do not require tumor cell replication. NF Bio is the first to develop a bacteria-based therapy for the treatment of NF2. We have demonstrated in animal models that i.t. injection of attenuated S. typhimurium decreases the volume of the injected tumor through direct cytotoxic and anti-angiogenic effects; importantly, it also induces a systemic immune response that targets distal tumors and a memory response that prevents further development of new lesions. This intervention has a lower risk of neurologic damage than operative resection due to the targeting mechanisms and engineered safety mechanisms that will be developed in this proposal. In the proposed Phase I work, NF Bio will develop a next-generation bacterial therapy that enhances direct tumor killing and induce immune-mediated killing. In future Phase II grant work, we will select a Development Candidate (DC) based on in vitro and in vivo data, and conduct toxicology and biodistribution studies to enable a US Investigational New Drug (IND) application.
2型神经纤维瘤病(NF 2)是一种罕见的遗传性疾病,在全球范围内影响约1/25,000的个体。 虽然通常是良性的,但这些肿瘤导致受影响个体的严重发病率和死亡率。几乎所有NF 2 患者失去听力,许多人失去行走甚至视力。NF 2患者死亡时的平均年龄 是36岁,其中许多人死于青春期或成年早期的疾病。NF 2是一种罕见适应症 并代表了一个主要的未满足的医疗需求,从而支持FDA快速通道指定。NF Bio估计值 NF 2商业机会,年销售额在高峰年超过10亿美元。NF 2治疗的成功也将 导致在其他良性和神经鞘瘤相关肿瘤如NF 1中进行测试。 手术切除和放射治疗是目前的治疗标准。然而,这些治疗方法有很大的 局限性。切除可导致严重的感觉丧失,包括耳聋、疼痛、面瘫和运动障碍。 功能障碍由于神经或脑干损伤的风险,切除也不总是可能的。放疗 由于恶性转化的风险,可能是禁忌的,并且通常不会消除 神经鞘瘤受影响的个体通常具有多个神经鞘瘤,肿瘤在整个生命中产生, 进一步增加了疾病相关的痛苦并限制了手术切除的效用。无获批 药物治疗和有限的临床试验管道。 NF Bio开发了一种NF 2细菌疗法,利用肿瘤内(i.t.)注射减毒S. 由神经外科医生,耳鼻喉科医生, 疼痛内科医生或介入放射科医生使用这种细菌治疗神经鞘瘤是合理的 沙门氏菌在高度血管化组织的缺氧区域生长,这是NF 2的标志 神经鞘瘤,并且其抗肿瘤细胞毒性机制不需要肿瘤细胞复制。 NF Bio是第一家开发用于治疗NF 2的细菌疗法的公司。我们已经在动物实验中证明了 模型,注射减毒S.鼠伤寒沙门氏菌可通过直接给药减少注射肿瘤的体积, 细胞毒性和抗血管生成作用;重要的是,它还诱导靶向远端 肿瘤和记忆反应,防止进一步发展新的病变。这种干预措施具有较低的 由于靶向机制和工程安全性,神经系统损伤风险高于手术切除 将在本提案中制定的机制。 在拟议的I期工作中,NF Bio将开发下一代细菌疗法, 杀伤并诱导免疫介导的杀伤。在未来的第二阶段拨款工作中,我们将选择一个发展候选人, (DC)基于体外和体内数据,进行毒理学和生物分布研究, 研究性新药(IND)申请。

项目成果

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GARY JAY BRENNER其他文献

GARY JAY BRENNER的其他文献

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{{ truncateString('GARY JAY BRENNER', 18)}}的其他基金

Mechanisms of Caspase-1 Mediated Schwannoma Regression
Caspase-1 介导神经鞘瘤消退的机制
  • 批准号:
    8703827
  • 财政年份:
    2012
  • 资助金额:
    $ 19.86万
  • 项目类别:
Mechanisms of Caspase-1 Mediated Schwannoma Regression
Caspase-1 介导神经鞘瘤消退的机制
  • 批准号:
    8421092
  • 财政年份:
    2012
  • 资助金额:
    $ 19.86万
  • 项目类别:
Mechanisms of Caspase-1 Mediated Schwannoma Regression
Caspase-1 介导神经鞘瘤消退的机制
  • 批准号:
    9125667
  • 财政年份:
    2012
  • 资助金额:
    $ 19.86万
  • 项目类别:
Mechanisms of Caspase-1 Mediated Schwannoma Regression
Caspase-1 介导神经鞘瘤消退的机制
  • 批准号:
    8554387
  • 财政年份:
    2012
  • 资助金额:
    $ 19.86万
  • 项目类别:
NMDA Receptor Phosphorylation and Trafficking after Pain
疼痛后 NMDA 受体磷酸化和运输
  • 批准号:
    7099536
  • 财政年份:
    2002
  • 资助金额:
    $ 19.86万
  • 项目类别:
NMDA Receptor Phosphorylation and Trafficking after Pain
疼痛后 NMDA 受体磷酸化和运输
  • 批准号:
    6508520
  • 财政年份:
    2002
  • 资助金额:
    $ 19.86万
  • 项目类别:
NMDA Receptor Phosphorylation and Trafficking after Pain
疼痛后 NMDA 受体磷酸化和运输
  • 批准号:
    6631457
  • 财政年份:
    2002
  • 资助金额:
    $ 19.86万
  • 项目类别:
NMDA Receptor Phosphorylation and Trafficking after Pain
疼痛后 NMDA 受体磷酸化和运输
  • 批准号:
    6931047
  • 财政年份:
    2002
  • 资助金额:
    $ 19.86万
  • 项目类别:
NMDA Receptor Phosphorylation and Trafficking after Pain
疼痛后 NMDA 受体磷酸化和运输
  • 批准号:
    6779216
  • 财政年份:
    2002
  • 资助金额:
    $ 19.86万
  • 项目类别:
DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY
微生物学和免疫学系
  • 批准号:
    2241228
  • 财政年份:
    1994
  • 资助金额:
    $ 19.86万
  • 项目类别:

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