ENGINEERED MICROBIAL THERAPEUTICS FOR METHIONINE RESTRICTION TREATMENT OF HERITABLE FORMS OF GLIOMA.

长期以来，系统蛋氨酸水平与癌症疾病的发生和进展有关，细胞代谢的变化使肿瘤细胞对氨基酸缺乏敏感。Petri Bio公司开发了一种新的治疗策略，使用微生物组兼容的细菌菌株作为代谢酶的表达载体。该公司的主要产品是一种活的生物治疗微生物，它可以产生蛋氨酸降解酶，可以口服，在被胃肠道系统吸收之前减少膳食中的蛋氨酸。在这里，Petri Bio公司将在匹兹堡大学Sameer Agnihotri博士实验室开发的弥漫性中线胶质瘤（DGM），弥漫性包容性脑桥胶质瘤（DIPG）的小鼠模型中评估这种候选治疗方法。Agnihotri博士的研究表明，经过基因改造携带组蛋白3基因特定突变的小鼠对蛋氨酸高度敏感，而组蛋白3基因是导致儿科患者DGM/DIPG的基因。在限制蛋氨酸饮食的情况下，荷瘤小鼠的寿命明显延长，这一策略与人类患者的依从性差和效果最小有关。成功证明Petri Bio的方法可以减少肿瘤负担并延长小鼠模型系统的寿命，将为继续开发和最终商业化提供令人信服的可行性数据。

Systemic methionine levels have long been implicated in cancer disease onset and progression, with changes in cellular metabolism rendering tumor cells sensitive to amino acid deficiencies. Petri Bio, Inc. has developed a novel therapeutic strategy, using microbiome-compatible bacterial strains as expression vectors for metabolic enzymes. The company’s lead product is a live biotherapeutic microbe which produces methionine degrading enzymes that can be taken orally, reducing dietary methionine before it is absorbed by the gastrointestinal system. Here, Petri Bio, Inc. will evaluate this candidate therapeutic in a murine model of form of diffuse midline glioma (DGM), diffuse inclusive pontine glioma (DIPG), developed in the laboratory of Sameer Agnihotri, PhD of the University of Pittsburgh. Dr. Agnihotri’s work indicates that mice engineered to carry specific mutations in the histone 3 gene known to be responsible for DGM/DIPG in pediatric patients, are highly sensitive to methionine. Tumor-bearing mice exhibit significantly increased lifespans when on a methionine-restrictive diet, a strategy associated with poor adherence and minimal effectiveness in human patients. Successfully demonstrating that Petri Bio’s approach reduces tumor burden and extends life span in this murine model system will provide compelling feasibility data toward continued development and eventual commercialization.