Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma

具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼

基本信息

项目摘要

Glaucoma is a neurodegenerative disease of the eye with an estimated prevalence of 80 million patients worldwide by 2020, at least 6 to 8 million becoming bilaterally blind. Elevated intraocular pressure (IOP) causing axonal degeneration of the optic nerve and progressive loss of retinal ganglion cells (RGCs) which are the characteristic hallmarks of glaucoma. Clinically, the only method of slowing glaucomatous vision loss is to reduce intraocular pressure (IOP), which is partially effective and doesn’t address susceptibility to RGC degeneration. Current therapy for glaucoma includes use of prostaglandin analogs based IOP lowering agents, however, about 10% of glaucoma patients don’t respond to these therapies. Brimonidine, an α2 agonist, eye-drop lowers IOP and is also neuroprotective, however it causes many side effects such as allergic reactions and corneal disorders. Along with IOP, age related decline in anti- oxidant enzymes in ocular tissues contributes to the death of both RGCs and trabecular meshwork (TM) cells, which is not addressed by available treatments. The nitric oxide (NO) system could potentially be targeted to enhance the aqueous outflow by relaxing the trabecular meshwork (TM) cells to lower IOP. Here, we propose to develop a robust hybrid NO donating and SOD mimetic compound encapsulated in PLGA nanoparticle which will prolong the duration of lowering IOP and also have neuroprotective effects. We have synthesized a novel bi-functional hybrid compound SA-2 with NO donor and SOD mimetic functional groups. Our preliminary results demonstrated that, a single eye drop of PLGA encapsulated SA-2 nanoparticles (SA-2-NPs) lowered IOP by 50% in a mouse glaucoma model. Additionally, compound SA-2 is highly neuroprotective both in ex vivo hypoxic insult of adult rat retinal explants and in in vivo mouse optic nerve crush model via intravitreal injection. Our goals are 1) to optimize the dose via toxicokinetic study of SA-2-NPs and determine the efficacy to lower IOP in two animal models: a mouse model of ocular hypertension (OHTN) induced by Ad5.TGFβ2 and in normotensive monkey eyes. 2) To delineate the biochemical mechanisms through which compound SA-2 protects both human TM cells and RGCs from glaucomatous changes. 3) To assess the topically administered SA-2-NPs for their ability to prevent RGC death in two models: a mouse model of optic nerve crush (traumatic injury) and a mouse model of ocular hypertension (chronic injury). Successful completion of the above proposed studies will provide information on the maximum effective dose of and frequency of dosing of SA-2-NPs that will be further evaluated in laser induced OHTN monkey model as our future goal and eventually will progress to human clinical trials. The results will have a major impact in the field with implications for developing novel non-prostaglandin therapeutics that have both IOP lowering and neuroprotective effects.
青光眼是一种眼部神经退行性疾病,估计有 8000 万患者患病 到 2020 年,全球至少有 6 至 800 万人双眼失明。眼压升高(IOP) 导致视神经轴突变性和视网膜神经节细胞(RGC)逐渐丧失 这是青光眼的特征性特征。临床上,唯一减缓青光眼发生的方法 视力下降是为了降低眼压(IOP),但这种方法是部分有效的,并不能解决问题 对 RGC 变性的易感性。目前青光眼的治疗包括使用前列腺素类似物 然而,约 10% 的青光眼患者对这些疗法没有反应。 溴莫尼定是一种 α2 激动剂,滴眼剂可降低眼压并具有神经保护作用,但它会导致许多 副作用,例如过敏反应和角膜疾病。与眼压一起,年龄相关的抗氧化能力下降 眼组织中的氧化酶导致 RGC 和小梁网 (TM) 死亡 细胞,这是现有治疗方法无法解决的问题。一氧化氮(NO)系统可能是 旨在通过放松小梁网 (TM) 细胞来降低眼压来增强房水流出。 在这里,我们建议开发一种强大的混合 NO 捐赠和 SOD 模拟化合物,封装在 PLGA纳米颗粒可延长降低眼压的持续时间,并具有神经保护作用。 我们合成了一种新型双功能杂化化合物 SA-2,具有 NO 供体和 SOD 模拟物 功能组。我们的初步结果表明,单滴 PLGA 胶囊 SA-2 纳米颗粒 (SA-2-NP) 在小鼠青光眼模型中使 IOP 降低 50%。此外, 化合物 SA-2 在成年大鼠视网膜外植体的离体缺氧损伤和 通过玻璃体内注射建立体内小鼠视神经挤压模型。我们的目标是 1) 优化剂量 通过 SA-2-NP 的毒代动力学研究,确定在两种动物模型中降低 IOP 的功效: Ad5.TGFβ2 诱导的高眼压症 (OHTN) 小鼠模型和血压正常的猴眼。 2) 描述化合物 SA-2 保护人类 TM 的生化机制 青光眼变化引起的细胞和 RGC。 3) 评估局部施用的 SA-2-NP 的效果 在两种模型中预防 RGC 死亡的能力:视神经挤压(创伤性损伤)的小鼠模型和 高眼压小鼠模型(慢性损伤)。顺利完成上述建议 研究将提供有关 SA-2-NP 的最大有效剂量和给药频率的信息 这将作为我们未来的目标在激光诱导 OHTN 猴子模型中进行进一步评估,并最终将 人体临床试验取得进展。研究结果将对该领域产生重大影响 开发具有降低眼压和神经保护作用的新型非前列腺素疗法 影响。

项目成果

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Suchismita Acharya其他文献

Suchismita Acharya的其他文献

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{{ truncateString('Suchismita Acharya', 18)}}的其他基金

A novel approach for prevention of Bronchopulmonary dysplasia in at-risk pre-term infants
预防高危早产儿支气管肺发育不良的新方法
  • 批准号:
    10765750
  • 财政年份:
    2023
  • 资助金额:
    $ 36.5万
  • 项目类别:
A novel approach for prevention of Bronchopulmonary dysplasia in at-risk pre-term infants
预防高危早产儿支气管肺发育不良的新方法
  • 批准号:
    10482142
  • 财政年份:
    2022
  • 资助金额:
    $ 36.5万
  • 项目类别:
A novel approach for prevention of Bronchopulmonary dysplasia in at-risk pre-term infants
预防高危早产儿支气管肺发育不良的新方法
  • 批准号:
    10616606
  • 财政年份:
    2022
  • 资助金额:
    $ 36.5万
  • 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
  • 批准号:
    10477236
  • 财政年份:
    2020
  • 资助金额:
    $ 36.5万
  • 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
  • 批准号:
    10684092
  • 财政年份:
    2020
  • 资助金额:
    $ 36.5万
  • 项目类别:
Sex differences in in vitro and in vivo glaucoma models may predict gender specific dose adjustment needs
体外和体内青光眼模型的性别差异可以预测性别特异性剂量调整需求
  • 批准号:
    10333877
  • 财政年份:
    2020
  • 资助金额:
    $ 36.5万
  • 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
  • 批准号:
    10226000
  • 财政年份:
    2020
  • 资助金额:
    $ 36.5万
  • 项目类别:

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