Ferreira Joao N A, Zheng Changyu, Lombaert Isabelle M A, Goldsmith Corinne M, Cotrim Ana P, Symonds Jennifer M, Patel Vaishali N, Hoffman Matthew P
Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA.
Translational Research Core, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA.
Mol Ther Methods Clin Dev. 2018 Feb 23;9:172-180. doi: 10.1016/j.omtm.2018.02.008. eCollection 2018 Jun 15.
Head and neck cancer patients treated with irradiation often present irreversible salivary gland hypofunction for which no conventional treatment exists. We recently showed that recombinant neurturin, a neurotrophic factor, improves epithelial regeneration of mouse salivary glands in culture after irradiation by reducing apoptosis of parasympathetic neurons. Parasympathetic innervation is essential to maintain progenitor cells during gland development and for regeneration of adult glands. Here, we investigated whether a neurturin-expressing adenovirus could be used for gene therapy to protect parasympathetic neurons and prevent gland hypofunction after irradiation. First, fetal salivary gland culture was used to compare the neurturin adenovirus with recombinant neurturin, showing they both improve growth after irradiation by reducing neuronal apoptosis and increasing innervation. Then, the neurturin adenovirus was delivered to mouse salivary glands , 24 hr before irradiation, and compared with a control adenovirus. The control-treated glands have ∼50% reduction in salivary flow 60 days post-irradiation, whereas neurturin-treated glands have similar flow to nonirradiated glands. Further, markers of parasympathetic function, including vesicular acetylcholine transporter, decreased with irradiation, but not with neurturin treatment. Our findings suggest that neurturin gene therapy prior to irradiation protects parasympathetic function and prevents irradiation-induced hypofunction.
接受放射治疗的头颈癌患者常常会出现不可逆的唾液腺功能减退，而目前尚无常规治疗方法。我们最近发现，神经营养因子重组神经营养素（neurturin）可通过减少副交感神经元的凋亡，改善照射后小鼠唾液腺在培养中的上皮再生。副交感神经支配对于腺体发育过程中维持祖细胞以及成年腺体的再生至关重要。在此，我们研究了表达神经营养素的腺病毒是否可用于基因治疗，以保护副交感神经元并预防照射后腺体功能减退。首先，利用胎儿唾液腺培养物将神经营养素腺病毒与重组神经营养素进行比较，结果表明它们均可通过减少神经元凋亡和增加神经支配来改善照射后的生长。然后，在照射前24小时将神经营养素腺病毒导入小鼠唾液腺，并与对照腺病毒进行比较。照射后60天，接受对照治疗的腺体唾液分泌量减少约50%，而接受神经营养素治疗的腺体唾液分泌量与未照射的腺体相似。此外，包括囊泡乙酰胆碱转运体在内的副交感神经功能标志物在照射后减少，但在神经营养素治疗后未减少。我们的研究结果表明，照射前进行神经营养素基因治疗可保护副交感神经功能并预防照射引起的功能减退。
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