Transplantation of hESC-derived otic progenitors into models of neuropathic deafness:long term analysis and safety

耳聋是一个主要的公共卫生问题，在英国有超过300万人患有中度至重度听力损失。如果我们包括轻度残疾的患者，这一数字将超过1 000万。事实上，大多数形式的耳聋都是渐进性的神经退行性疾病，涉及感觉毛细胞（将声音转化为电信号的细胞）及其相关神经元（负责将信号传递到大脑）的损失。这两种细胞都只在子宫内产生，因此如果它们受损，就不会被替换，听力损失是不可逆转的。唯一可用的治疗方法是人工耳蜗植入，但它需要保留感觉神经元才能发挥作用。当损伤主要发生在神经元时，在一种称为听神经病的情况下，治疗选择非常有限，植入物性能很差。从理论上讲，基于干细胞的疗法可以用已经丢失的细胞类型重新填充失聪的耳朵，并为功能恢复提供新的机会。我们最近已经确定，移植人耳祖细胞，在实验室中产生的人胚胎干细胞，可以取代失去的听觉神经元在沙鼠，并引起一定程度的功能恢复。该项目的目的是评估移植的人类干细胞在听觉神经受损的动物中的长期行为和生物安全性，类似于在人类听觉神经病中观察到的情况。待应用的细胞已经在培养中进行了广泛的研究，我们有证据表明，当用适当的条件处理时，它们可以分化为功能细胞。我们正在进行更多的体外实验，试图了解它们的分子和功能特性。但是，为了评估与宿主的相互作用及其可能引发的反应，以及它们的有益效果是否长期持续，它们必须在动物模型中进行测试。我们想要解决的问题涉及实现最大恢复所需的细胞数量，如果功能恢复是永久性的，以及传递到耳蜗中的细胞是否可以扩散到其他组织中。此外，重要的是要弄清楚它们是否会引起肿瘤，或者有其他不必要的影响。我们工作中需要强调的一个重要问题是，这些实验将使用人类细胞进行，这是实际假定的治疗工具。从这些研究中获得的信息应促进其未来在人类临床试验中的应用和耳聋治疗的发展。

Deafness is a major public health issue, with more than 3 million people in the UK suffering a moderate to profound hearing loss. The numbers rise to more than 10 million if we include sufferers of mild impairments. Most forms of deafness are, in fact, progressive, neurodegenerative disorders which involve loss of sensory hair cells (cells that converts sounds into an electrical signal) and their associated neurons (responsible to take the signal to the brain). Both these cells are only produced in the womb, therefore if they become damaged are not replaced and hearing loss is irreversible. The only treatment available is the cochlear implant, but it needs the preservation of the sensory neurons to function. When the damage occurs primarily at the neurons, in a condition known as auditory neuropathy, the therapeutic options are very limited and implant performance is poor. A stem cell-based therapy could, in theory, repopulate the deaf ear with the cell types that have been lost and offer new opportunities for functional recovery. We have recently established that transplantation of human otic progenitors, generated in the laboratory from human embryonic stem cells, can replace lost auditory neurons in the gerbil and elicit a level of functional restoration. The aim of this project is to assess the long-term behaviour and biosafety of transplanted human stem cell in animals with a damaged auditory nerve, resembling the condition observed in human auditory neuropathies. The cells to be applied have been extensively studied in culture, and we have evidence that they can differentiate into functional cells when treated with the appropriated conditions. We are performing more experiments in vitro, trying to understand their molecular and functional properties. But in order to evaluate the interaction with a host and the responses they may trigger, as well as if their beneficial effects are sustained long-term, they would have to be tested in an animal model. Questions we would like to address involve the number of cells needed to achieve maximum recovery, if the functional recovery is permanent and whether the cells delivered into the cochlea can spread into other tissues. Moreover, it will be important to find out if they can originate tumours, or have other unwanted effects.An important issue to highlight with our work is that these experiments will be performed with human cells, the actual putative therapeutic tools. The information obtain from these studies should advance their future application in human clinical trials and the development of a therapy for deafness.