New method to treat or prevent corneal graft rejection

项目摘要 角膜移植是世界范围内最常见的实体器官移植， 排斥是移植失败的主要原因。皮质类固醇滴眼液必须经常应用，以防止移植 排斥反应和救援移植物显示排斥反应的早期迹象，因为局部给药的药物进行 清除迅速，眼部生物利用度差。然而，长期频繁给药与 患者依从性低，依从者有眼内压（IOP）升高的风险， 引起青光眼。我们提出了一种新的方法，提供持续的皮质类固醇输送低，但 有效水平，消除患者的治疗负担，提高皮质类固醇的安全性。我们 开发了含有高载量地塞米松磷酸钠（DSP）的可生物降解纳米颗粒 它可以通过与外科医生在角膜移植结束时使用DSP相同的途径给药 手术、结膜下（SCT）注射。此外，负载DSP的纳米颗粒（DSP-NP）被涂覆有 聚乙二醇（PEG），以尽量减少眼睛的炎症反应，与局部滴剂相比， 在动物模型中不会引起IOP升高。初步的实验结果表明DSP-NP是有效的 用于预防和治疗大鼠模型中移植物排斥的早期迹象。在这里，我们的目标是发展更长的时间- 可安全有效地预防和治疗角膜移植排斥反应的长效制剂， 一个月一次注射。如果成功，这种方法将大大改善角膜移植 患者护理和预后。在目标1中，我们将确认批次重现性，确定最大耐受性， 剂量（MTD），并评估眼部药代动力学（PK）。然后将检测两种先导制剂的剂量 在我们的大鼠移植物排斥模型中预防和治疗的依赖性功效在目的2中。最后我们将 在家兔中进行至少一种先导DSP-NP制剂的详细安全性和药代动力学研究， 目的3：促进未来的发展和潜在的临床翻译。

PROJECT SUMMARY Corneal transplantation is the most common solid organ transplantation worldwide, and immunological graft rejection is the main cause of graft failure. Corticosteroid eye drops must be applied frequently to prevent graft rejection and rescue grafts that show early signs of rejection, because topically administered drugs undergo rapid clearance and have poor ocular bioavailability. However, long-term, frequent dosing is associated with low patient compliance, and those that comply have risk of increased intraocular pressure (IOP), which can cause glaucoma. We propose a new method for providing sustained corticosteroid delivery at low, but efficacious levels, removing the treatment burden from patients and improving the safety of corticosteroids. We developed biodegradable nanoparticles containing high loadings of dexamethasone sodium phosphate (DSP) that can be administered by the same route that surgeons administer DSP at the end of corneal transplant surgery, subconjunctival (SCT) injection. Further, DSP-loaded nanoparticles (DSP-NP) are coated with polyethylene glycol (PEG) to minimize inflammatory reactions in the eye, and in contrast to topical drops, do not cause an increase in IOP in animal models. Our preliminary results demonstrate that DSP-NP are effective for both preventing and treating early signs of graft rejection in a rat model. Here, our aim is to develop longer- lasting formulations that can safely and effectively prevent and treat corneal graft rejection, for as long as 3 months with a single injection. If successful, this approach would significantly improve corneal transplant patient care and prognosis. In Aim 1, we will confirm batch reproducibility, determine the maximum tolerated dose (MTD), and assess ocular pharmacokinetics (PK). The two lead formulations will then be tested for dose dependent efficacy for prevention and treatment in our rat model of graft rejection in Aim 2. Finally, we will carry out detailed safety and pharmacokinetics studies of at least one lead DSP-NP formulation in rabbits in Aim 3 to facilitate future development and potential clinical translation.