Pneumografting - a novel cell-based therapy for emphysema

描述(申请人提供)：最近的研究表明，有助于损伤后肺部愈合的修复细胞也具有再生能力。虽然出生后肺再生的生物学机制还不是很清楚，但机械预应激似乎是组织再生发生的绝对必要条件。肺气肿是一种以组织破坏为特征的疾病，是基于细胞的治疗的潜在靶点。这种疾病与：1)常驻修复细胞的丢失；2)传递预应激信号的细胞外基质的丢失；3)预应激本身的丢失，而预应激本身正是触发再生反应所需的信号。尽管这些因素阻碍了肺气肿再生治疗策略的发展，但我们实验室的初步研究表明，利用与生物相容聚合物中的载体分子络合的成纤维细胞生长因子家族成员来调节间充质和上皮细胞的增殖可以促进实质组织的扩张。聚合物支架是一种含有空气的泡沫，其机械性能类似于健康的肺组织，它有效地将压力传递到修复/祖细胞，以促进增殖和重塑。这里提出的研究将检验这样的假设：1)肺气肿出生后肺组织的治疗性生长可以通过使用生长因子增强肺的先天修复反应来实现，在局部轻度损伤后，使用生长因子引导内源性修复肺细胞；以及2)这种反应的大小可以通过改变预应激来调节，使用支气管镜肺减容疗法来增加跨肺压。我们打算在一项由医生赞助的新药应用研究中，将这种称为充气植入术的方法推进到人体试验中。

DESCRIPTION (provided by applicant): Recent studies suggest that reparative cells which contribute to healing in the lung following injury also possess regenerative capacity. Although the biology of post-natal lung regeneration is not well understood, mechanical pre-stress appears to be an absolute requirement for tissue regeneration to occur. Emphysema, a disease characterized by tissue destruction, is a potential target for cell-based therapy. This disease is associated with: 1) loss of resident reparative cells; 2) loss of the extracellular matrix that transmits pre-stress signaling; 3) and loss of pre-stress itself, the very signal required to trigger regenerative responses. Although these factors represent obstacles to the development of regenerative therapeutic strategies for emphysema, preliminary studies in our lab show that modulation of mesenchymal and epithelial cell proliferation using members of the fibroblast growth factor family complexed to carrier molecules in a biocompatible polymer can promote expansion of parenchymal tissues. The polymer scaffold, an air containing foam with mechanical properties similar to healthy lung tissue, effectively transmits stress to reparative/progenitor cells to promote proliferation and remodeling. Studies proposed here will test the hypothesis that 1) therapeutic post-natal lung tissue growth in emphysema can be achieved by augmenting the lung's innate healing response using growth factors to direct endogenous reparative lung cells following a localized mild injury; and that 2) the magnitude of this response can be modulated by altering pre-stress using concomitant bronchoscopic lung volume reduction therapy to increase transpulmonary pressures. We intend to advance this approach, known as pneumografting, into human trials under a physician-sponsored Investigation New Drug Application.