Development of recombinant surfactant protein D therapy to prevent neonatal chronic lung disease

早产儿的肺不成熟，缺乏肺表面活性剂，肺表面活性剂通常由肺产生，对正常呼吸至关重要。因此，早产儿在出生后经常需要额外的帮助来呼吸，并且在新生儿重症监护中依赖于具有呼吸机和正压设备的人工呼吸支持，以防止他们的肺塌陷。目前，早产儿接受来自动物肺的表面活性剂替代疗法。通过稳定他们的肺部和改善他们的呼吸能力，这在挽救他们的生命方面非常成功。然而，目前临床使用的表面活性剂疗法不包含正常人表面活性剂的所有组分，并且现在出生后存活的小于28周妊娠的婴儿中有一半以上继续发展慢性肺部炎症和新生儿慢性肺病（nCLD），这使得婴儿依赖于氧气并且对常见的儿童病毒感染的危及生命的反应高度敏感，哮喘和其他慢性肺部问题。在目前的表面活性剂治疗中缺少的天然表面活性剂的组分是表面活性剂蛋白D（SP-D），这是一种天然的肺防御蛋白，在保持肺部健康和免受感染和炎症方面起着重要作用。事实上，SP-D在控制肺部炎症方面非常重要，以至于缺乏SP-D基因的小鼠自发地发展慢性肺部炎症，导致肺气肿，肺组织的破坏在吸烟者和早产儿中很常见，这些早产儿的肺部不成熟并因需要正压通气而受损。SP-D已被证明可以减少早产羔羊肺部的炎症。我们已经能够产生SP-D的功能片段（rfhSP-D），充分表征其结构，并表明它可以减少人类疾病动物模型中的炎症。rfhSP-D治疗不仅可以纠正缺乏SP-D的小鼠的肺气肿，而且rfhSP-D还可以有效减少细菌、病毒、真菌和寄生虫感染模型中的炎症以及常见真菌和屋尘螨过敏原引发的肺部炎症。我们的目标是开发这种天然人类表面活性蛋白片段作为一种新疗法，以补充目前给予早产儿的表面活性剂治疗，看看这是否有助于降低早产后慢性肺部疾病的高发病率。为此，我们必须首先将rfhSP-D的生产规模扩大到人类治疗所需的安全标准，然后进行临床试验，看看婴儿是否可以安全地使用这种额外的缺失表面活性蛋白进行治疗。如果这种天然蛋白质被证明是安全的，并且可以像目前的表面活性剂治疗一样输送到早产儿的肺部，这将有助于确定下一阶段临床测试的适当剂量方案，以确定用这种额外的蛋白质补充目前的表面活性剂治疗是否有助于降低早产儿慢性肺部问题的发生率。

Premature infants have immature lungs which lack lung surfactant which is normally produced by the lungs and is essential for normal breathing. Premature infants therefore frequently require additional help to breathe after birth and are reliant on artificial respiratory support with ventilators and positive pressure devices in neonatal intensive care to keep their lungs from collapsing. Currently, babies born early receive surfactant replacement therapy which is derived from the lungs of animals. This has been very successful in saving their lives by stabilising their lungs and improving their ability to breathe. However current surfactant therapies in clinical use do not contain all of the components of normal human surfactant and more than half of babies now surviving after birth at less than 28 weeks gestation go on to develop chronic lung inflammation and neonatal chronic lung disease (nCLD), which leaves infants oxygen dependent and highly susceptible to life threatening reactions to common childhood viral infections, asthma and other chronic lung problems in later life. A component of the natural surfactant that is missing in current surfactant therapy is surfactant protein D (SP-D), a natural lung defence protein which plays an important role in keeping the lungs healthy and free from infection and inflammation. In fact, SP-D is so important in controlling lung inflammation that mice lacking the gene for SP-D spontaneously develop chronic lung inflammation causing emphysema, a destruction of the lung tissue that is common in smokers and in preterm babies whose lungs are immature and damaged by the need for positive pressure ventilation. SP-D has been shown to reduce inflammation in the lungs of preterm lambs. We have been able to produce a functional fragment of SP-D (rfhSP-D), have fully characterised its structure and shown that it works to reduce inflammation in animal models of human disease. Not only does treatment with rfhSP-D correct the emphysema in mice lacking SP-D, but the rfhSP-D is also effective in reducing inflammation in models of infection with bacteria, viruses, fungi and parasites as well as lung inflammation triggered by common fungal and house dust mite allergens. We aim to develop this fragment of the natural human surfactant protein as a new therapy to supplement surfactant treatments currently given to preterm babies, to see if this can help reduce the high incidence of chronic lung disease after preterm birth. To do this, we must first scale up production of the rfhSP-D to the required safety standards for human treatment and then carry out a clinical trial to see if babies can be treated safely with this additional missing surfactant protein. If this natural protein is shown to be safe and deliverable to the lungs of premature babies like current surfactant therapy, this will help determine the appropriate dosing regime for the next stage of clinical testing to see if supplementing current surfactant treatment with this extra protein will help reduce the incidence of chronic lung problems in babies born too early.