CERE-120可预防猪唾液腺辐射诱导的功能减退并恢复免疫稳态。

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核心技术专利：CN118964589B侵权必究

Suppr 超能文献

核心技术专利：CN118964589B侵权必究

Lombaert Isabelle M A, Patel Vaishali N, Jones Christina E, Villier Derrick C, Canada Ashley E, Moore Matthew R, Berenstein Elsa, Zheng Changyu, Goldsmith Corinne M, Chorini John A, Martin Daniel, Zourelias Lee, Trombetta Mark G, Edwards Paul C, Meyer Kathleen, Ando Dale, Passineau Michael J, Hoffman Matthew P

Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA.

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.

Mol Ther Methods Clin Dev. 2020 Jul 31;18:839-855. doi: 10.1016/j.omtm.2020.07.016. eCollection 2020 Sep 11.

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis.

唾液腺功能减退会给接受放射治疗的头颈癌患者带来严重的发病率并降低生活质量。预防功能减退是一项尚未满足的治疗需求。我们使用了一种表达人神经营养因子神经营养素（CERE-120）的腺相关病毒2型（AAV2）载体，在照射前或照射后（IR）治疗小鼠颌下腺。照射前而非照射后用CERE-120治疗可预防功能减退。RNA测序（RNA-seq）分析显示，与纤维化以及先天性和体液免疫反应相关的基因表达降低。然后，我们使用了一个在照射前用CERE-120治疗的小型猪模型，并比较了对侧未照射腺体的结果。基因表达、形态学和免疫染色分析显示，与照射相关的免疫反应降低，分泌机制得到改善。CERE-120可预防照射引起的功能减退并恢复免疫稳态，并且对侧腺体对损伤或治疗存在协同反应。CERE-120基因治疗是一种对头颈癌患者有潜力的治疗方法，可影响神经元、免疫和上皮细胞之间的通讯，以预防照射引起的唾液功能减退并恢复免疫稳态。