Antisense Morpholino Oligomers to Treat Retinopathy

反义吗啉寡聚物治疗视网膜病

• 批准号: 6690923
• 负责人: GAYATHRI R DEVI
• 金额: $ 10万
• 依托单位: AVI BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690923
• 关键词: angiogenesis; angiogenesis inhibitors; antisense nucleic acid; dosage; drug administration routes; drug discovery /isolation; eye disorder chemotherapy; eye pharmacology; gene expression; genetic translation; hyperoxia; integrins; laboratory mouse; morpholine; nucleic acid sequence; retina disorder

DESCRIPTION (provided by applicant): The broad, long-term objectives of the application are to develop antisense inhibitors of retinopathy and document their mechanism(s) of action. Retinopathy is a significant cause of eye disease and has a major impact on development, learning, communicating, working, health, and quality of life for affected individuals. This application focuses on the inhibition of retinal neovascularization using antisense oligomers directed against endothelial cell alphav integrins, using a mouse model of retinopathy of prematurity. Alphav integrins are highly up-regulated during angiogenesis, and pharmacologic inhibitors of alphav integrins prevent angiogenesis in vivo. Whereas small organic molecules, synthetic peptides, and monoclonal antibodies have been used in the past to inhibit av integrin function, this application proposes to use antisense oligomer inhibition of alphav integrin expression. Preliminary studies show that antisense oligomers directed against integrin alphav inhibit retinal neovascularization in mice in a sequence-specific manner. Furthermore, the specificity of antisense oligomers holds the promise of minimal side-effects compared to previous pharmacologic inhibitors. The specific aims are: I - To identify an alphav antisense oligomer sequence that effectively inhibits translation of human and mouse av integrin. II - To identify an optimal dose and route of administration of the alphav antisense PMO identified in Aim I that effectively inhibits neovascularization in the retina of ROP mice. This will be achieved by screening a series of antisense phosphorodiamidate morpholino oligomers using in vitro alphav translation assays and an in vivo mouse model of retinopathy of prematurity. The primary goal of this grant is to identify the optimal antisense alphav PMO, dose and schedule that maximally decreases alpha V expression and inhibits retinopathy of prematurity.

描述（由申请人提供）：申请的广泛，长期目标是发展视网膜病的反义抑制剂，并记录其作用机制。视网膜病是引起眼科疾病的重要原因，并对受影响的个体的发展，学习，沟通，工作，健康，健康和生活质量产生了重大影响。该应用的重点是使用针对内皮细胞alphav整联蛋白的反义低聚物对视网膜新血管化的抑制，并使用早产视网膜病变的小鼠模型。在血管生成过程中，alphav整联蛋白高度上调，α整联蛋白的药理学抑制剂可预防体内血管生成。尽管过去已经使用了小的有机分子，合成肽和单克隆抗体来抑制AV整合素的功能，但该应用建议使用反义寡聚物抑制alphav整合素表达。初步研究表明，针对整联蛋白alphav的反义寡聚物以序列特异性方式抑制小鼠的视网膜新血管形成。此外，与以前的药理抑制剂相比，反义低聚物的特异性具有最小的副作用的希望。具体目的是： i-确定Alphav反义寡聚序列，可有效抑制人和小鼠AV整合素的翻译。 ii-确定在AIM I中鉴定出的Alphav反义PMO的最佳剂量和给药途径，该AIM I有效地抑制了ROP小鼠视网膜中的新生血管形成。 这将通过使用体外Alphav翻译测定法和早产视网膜病变的体内小鼠模型来筛选一系列反义磷酸缩补的磷矩阵寡聚物。 该赠款的主要目的是确定最佳的反义Alphav PMO，剂量和时间表，以最大程度地降低Alpha V表达并抑制早产性视网膜病变。

项目成果

Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis.

• DOI: 10.3389/fcimb.2018.00311
• 发表时间: 2018
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Singh M;Khan RS;Dine K;Das Sarma J;Shindler KS
• 通讯作者: Shindler KS

Different mechanisms of inflammation induced in virus and autoimmune-mediated models of multiple sclerosis in C57BL6 mice.

• DOI: 10.1155/2013/589048
• 发表时间: 2013
• 期刊: BioMed research international
• 作者: Kishore A;Kanaujia A;Nag S;Rostami AM;Kenyon LC;Shindler KS;Das Sarma J
• 通讯作者: Das Sarma J

Mouse hepatitis virus infection upregulates genes involved in innate immune responses.

• DOI: 10.1371/journal.pone.0111351
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chatterjee D;Addya S;Khan RS;Kenyon LC;Choe A;Cohrs RJ;Shindler KS;Sarma JD
• 通讯作者: Sarma JD

SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease.

• DOI: 10.1186/2051-5960-2-3
• 发表时间: 2014-01-02
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Khan RS;Dine K;Das Sarma J;Shindler KS
• 通讯作者: Shindler KS

Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model.

• DOI: 10.1038/srep41768
• 发表时间: 2017-01-31
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Khan RS;Dine K;Bauman B;Lorentsen M;Lin L;Brown H;Hanson LR;Svitak AL;Wessel H;Brown L;Shindler KS
• 通讯作者: Shindler KS