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
- 来源:
- 关键词:Acoustic NeuromaAdolescenceAffectAgeAllograftingAnimal ModelApplications GrantsAreaAttenuatedBacteriaBenignBenign SchwannomaBiodistributionBiologicalBlood VesselsBrain StemCaringCause of DeathCellsCessation of lifeClinical DataClinical TreatmentClinical TrialsDataDevelopmentDiseaseDistalEngineeringEpendymomaEquilibriumExcisionFDA approvedFacial paralysisFutureGenerationsGoalsGrantGrowthHearingHumanHypoxiaImmuneImmune responseImmunologicsIn VitroIndividualInjectionsInterventionInvestigational New Drug ApplicationLeadLesionLifeMagnetic Resonance ImagingMalignant - descriptorMalignant NeoplasmsMeasuresMediatingMedicalMedicineMemoryModelingMorbidity - disease rateMusMycobacterium bovisNF1 geneNeoplasmsNerveNervous System TraumaNeurilemmomaNeurofibromatosis 2NeurosurgeonOperative Surgical ProceduresOrphanOtolaryngologistPainParentsPatientsPeripheral Nervous SystemPharmacologic SubstancePhasePhysiciansProductionPropertyRadiation therapyResectedRiskSafetySalesSalmonellaSalmonella typhimuriumSensorySmall Business Technology Transfer ResearchTestingTherapeutic EffectTissuesToxic effectToxicologyTranslationsTumor Cell InvasionTumor ImmunityUltrasonographyValidationVirusWalkingWorkXenograft procedureadaptive immune responsebasecancer therapycell killingchemotherapeutic agentcytokinecytotoxiccytotoxicitydeafnessefficacy testingemerging adulthearing impairmenthigh riskimage guidedin vivoinnovationmacrophagemeningiomamortalitymotor disordernanobodiesneoplastic cellneurofibromanext generationnon-muscle invasive bladder cancernovelnovel therapeuticspre-clinicalpreventprogrammed cell death ligand 1radiologistrare genetic disorderresponsesafety engineeringsuccesstumor
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 (NF2) 是一种罕见的遗传性疾病,全球约 25,000 人中就有 1 人受到影响。
虽然这些肿瘤通常是良性的,但会导致受影响个体严重的发病率和死亡率。几乎所有 NF2
患者失去听力,许多人失去行走能力,甚至失去视力。 NF2患者的平均死亡年龄
36 岁,其中许多人在青春期或成年早期死于疾病。 NF2 是孤儿适应症
代表了一项重大的未满足的医疗需求,从而支持 FDA 快速通道指定。 NF生物估计
NF2 商业机会年峰值销售额超过 10 亿美元。 NF2 治疗的成功也将
导致对其他良性和神经鞘瘤相关肿瘤(如 NF1)进行检测。
手术切除和放射治疗是当前的护理标准。然而,这些治疗方法有很大的
限制。切除可导致严重的感觉丧失,包括耳聋、疼痛、面瘫和运动能力
功能障碍。由于存在神经或脑干损伤的风险,切除术也不总是可能的。放射治疗
由于存在恶性转化的风险,可能会被禁忌,并且通常不会消除
神经鞘瘤。受影响的个体通常患有多发性神经鞘瘤,肿瘤在一生中都会出现,
进一步增加与疾病相关的痛苦并限制手术切除的效用。没有经过批准的
药物治疗和有限的临床试验渠道。
NF Bio 开发了一种 NF2 细菌疗法,利用瘤内 (i.t.) 注射减毒的金黄色葡萄球菌。
鼠伤寒,由神经外科医生、耳鼻喉科医生以图像引导方式(MRI 或超声波)进行治疗,
疼痛医学医师或介入放射科医生使用这种细菌疗法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大量繁殖,这是 NF2 的标志
神经鞘瘤,其抗肿瘤细胞毒性机制不需要肿瘤细胞复制。
NF Bio 是第一个开发基于细菌的疗法来治疗 NF2 的公司。我们已经在动物身上证明了
它的模型注射减毒鼠伤寒沙门氏菌可通过直接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,它还能诱导针对远端的全身免疫反应
肿瘤和阻止新病变进一步发展的记忆反应。这种干预措施的效果较低
由于靶向机制和工程安全性,神经系统损伤的风险高于手术切除
本提案中将制定的机制。
在拟议的一期工作中,NF Bio 将开发一种增强直接肿瘤治疗的下一代细菌疗法
杀伤并诱导免疫介导的杀伤。在未来的第二阶段资助工作中,我们将选择一名开发候选人
(DC) 基于体外和体内数据,并进行毒理学和生物分布研究,以使美国
研究性新药 (IND) 申请。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
GARY JAY BRENNER其他文献
GARY JAY BRENNER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Identification of Prospective Predictors of Alcohol Initiation During Early Adolescence
青春期早期饮酒的前瞻性预测因素的鉴定
- 批准号:
10823917 - 财政年份:2024
- 资助金额:
$ 19.86万 - 项目类别:
Socio-Emotional Characteristics in Early Childhood and Offending Behaviour in Adolescence
幼儿期的社会情感特征和青春期的犯罪行为
- 批准号:
ES/Z502601/1 - 财政年份:2024
- 资助金额:
$ 19.86万 - 项目类别:
Fellowship
Reasoning about Spatial Relations and Distributions: Supporting STEM Learning in Early Adolescence
空间关系和分布的推理:支持青春期早期的 STEM 学习
- 批准号:
2300937 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Continuing Grant
Cognitive and non-cognitive abilities and career development during adolescence and adult development: from the perspective of genetic and environmental structure
青春期和成人发展期间的认知和非认知能力与职业发展:从遗传和环境结构的角度
- 批准号:
23K02900 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Does social motivation in adolescence differentially predict the impact of childhood threat exposure on developing suicidal thoughts and behaviors
青春期的社会动机是否可以差异预测童年威胁暴露对自杀想法和行为的影响
- 批准号:
10785373 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Mapping the Neurobiological Risks and Consequences of Alcohol Use in Adolescence and Across the Lifespan
绘制青春期和整个生命周期饮酒的神经生物学风险和后果
- 批准号:
10733406 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Thalamo-prefrontal circuit maturation during adolescence
丘脑-前额叶回路在青春期成熟
- 批准号:
10585031 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
The Role of Sleep in the Relationships Among Adverse Childhood Experiences, Mental Health Symptoms, and Persistent/Recurrent Pain during Adolescence
睡眠在不良童年经历、心理健康症状和青春期持续/复发性疼痛之间关系中的作用
- 批准号:
10676403 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Interdisciplinary Perspectives on the Politics of Adolescence and Democracy
青少年政治与民主的跨学科视角
- 批准号:
EP/X026825/1 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Research Grant
Harnessing digital data to study 21st-century adolescence
利用数字数据研究 21 世纪青春期
- 批准号:
MR/X028801/1 - 财政年份:2023
- 资助金额:
$ 19.86万 - 项目类别:
Research Grant