Nanoparticle & AAV Approaches to Rapid Onset, Stable Retinal Gene Therapy

纳米粒子

• 批准号: 7500698
• 负责人: Jijing Pang
• 金额: $ 21.54万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500698
• 关键词: Age; Animal Model; Behavior; Coupled; Cyclic GMP; DNA; DNA Transposons; Defect; Exhibits; Gene Delivery; Genes; Goals; Lead; Link; Modeling; Mus; Mutation; Phenotype; Photons; Polyethyleneimine; Property; Recombinants; Retinal; Retinal Cone; Retinal Diseases; Retinal Dystrophy; Side; Signal Transduction; Sleeping Beauty; Structure; System; Techniques; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Vertebrate Photoreceptors; Vision; absorption; adeno-associated viral vector; base; design; gene delivery system; gene therapy; mouse model; mutant; nanoparticle; neuronal cell body; phosphoric diester hydrolase; photoreceptor degeneration; ranpirnase; relating to nervous system; research study; response; retinal rods; therapeutic gene; therapy duration; treatment duration; vector

DESCRIPTION (provided by applicant): Cyclic guanosine monophosphate (cGMP) is a key messenger molecule that links absorption of photons to neural signaling in the vertebrate photoreceptor. Naturally occurring mutations of the ¿-subunit of PDE (PDE¿) gene in rods leads to rapid photoreceptor degeneration in rd mice. A new mouse model with PDE¿ mutation, rd10 mouse, in which rod photoreceptor degeneration initiates at about P16, with only cone cell bodies remaining at P30, will be employed to test if in time correction of mutant gene can lead to long-term stable retinal rescue. This requires a very rapid onset of therapeutic genes, which is a challenge for conventional vectors. In side-by-side experiments we propose to test for therapy in the rd10 mouse using AAV vector and DNA nanoparticle (LPEI) approaches to retinal gene delivery, both separately and in combination. In addition we propose to test the Sleeping Beauty (SB) transposon system via the DNA/LPEI nanoparticle approach as a way to combine the advantages of both the vector and nanoparticle techniques in a single system. Specific Aim 1. Test the therapeutic efficacy of AAV delivered PDE¿ in the rd10 mouse. Specific Aim 2. Test the therapeutic efficacy of DNA/LPEI nanoparticle delivered PDE¿ in the rd10 mouse. Specific Aim 3. Test the therapeutic efficacy of combined AAV + DNA/LPEI nanoparticle delivered PDE¿ in the rd10 mouse. Specific Aim 4. Test the therapeutic efficacy of Sleeping Beauty transposon DNA/LPEI nanoparticle delivered PDE¿ in the rd10 mouse. Our overall aim is to determine by comparison of these four alternatives for retinal gene delivery which achieves the most effective and safest therapy in this challenging, rapid onset model of recessive RP. Our ultimate goal is to establish a retinal gene delivery system that is fast, of long duration and can accommodate large therapeutic cDNAs. Our overall aim is to determine which of four alternatives for retinal gene delivery of the PDE¿ gene achieves the most effective and safest therapy in this challenging, rapid onset model of recessive RP, the rd10 mouse. Theses alternatives include AAV alone, DNA/LPEI nanoparticle alone, AAV combined with DNA/LPEI nanoparticle, and the Sleeping Beauty transposon DNA/LPEI nanoparticle. Our ultimate goal is to establish a retinal gene delivery system that is fast, of long duration and can accommodate large therapeutic cDNAs.

描述（由申请人提供）：环鸟苷单磷酸（cGMP）是脊椎动物光感受器中连接光子吸收和神经信号的关键信使分子。视杆细胞中PDE -亚基（PDE -）基因的自然突变导致rd小鼠的快速光感受器变性。在PDE¿突变小鼠模型rd10小鼠中，杆状光感受器在P16左右开始变性，P30仅保留锥体细胞体，将用于测试及时纠正突变基因是否可以导致长期稳定的视网膜拯救。这需要非常迅速地启动治疗性基因，这对传统载体来说是一个挑战。在并排实验中，我们建议在rd10小鼠中测试使用AAV载体和DNA纳米颗粒（LPEI）方法进行视网膜基因传递的治疗，无论是单独的还是联合的。此外，我们建议通过DNA/LPEI纳米粒子方法测试睡美人（SB）转座子系统，作为在单个系统中结合载体和纳米粒子技术优势的一种方法。具体目标检测AAV给药PDE¿对rd10小鼠的治疗效果。具体目标2。检测DNA/LPEI纳米颗粒对rd10小鼠PDE¿的治疗效果。具体目标3。检测AAV + DNA/LPEI纳米颗粒联合给药PDE¿对rd10小鼠的治疗效果。具体目标测试睡美人转座子DNA/LPEI纳米颗粒对rd10小鼠PDE¿的治疗效果。我们的总体目标是通过比较这四种视网膜基因传递的选择，确定在这种具有挑战性的，快速发病的隐性RP模型中实现最有效和最安全的治疗。我们的最终目标是建立一种快速、持续时间长、可以容纳大量治疗性cdna的视网膜基因传递系统。我们的总体目标是确定四种替代PDE基因的视网膜基因传递在这种具有挑战性的，快速发病的隐性RP模型，rd10小鼠中实现最有效和最安全的治疗。这些替代方案包括单独AAV、单独DNA/LPEI纳米颗粒、AAV与DNA/LPEI联合纳米颗粒和睡美人转座子DNA/LPEI纳米颗粒。我们的最终目标是建立一种快速、持续时间长、可以容纳大量治疗性cdna的视网膜基因传递系统。

项目成果

Self-complementary AAV5 vector facilitates quicker transgene expression in photoreceptor and retinal pigment epithelial cells of normal mouse.

• DOI: 10.1016/j.exer.2010.01.011
• 发表时间: 2010-05
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Kong, Fansheng;Li, Wensheng;Li, Xia;Zheng, Qinxiang;Dai, Xufeng;Zhou, Xiangtian;Boye, Sanford L.;Hauswirth, William W.;Qu, Jia;Pang, Ji-Jing
• 通讯作者: Pang, Ji-Jing

Trans-Corneal Subretinal Injection in Mice and Its Effect on the Function and Morphology of the Retina.

小鼠经角膜视网膜下注射及其对视网膜功能和形态的影响

• DOI: 10.1371/journal.pone.0136523
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Qi Y;Dai X;Zhang H;He Y;Zhang Y;Han J;Zhu P;Zhang Y;Zheng Q;Li X;Zhao C;Pang J
• 通讯作者: Pang J

Histone Deacetylases Inhibitors in the Treatment of Retinal Degenerative Diseases: Overview and Perspectives.

组蛋白脱乙酰酶抑制剂治疗视网膜退行性疾病：概述和展望

• DOI: 10.1155/2015/250812
• 发表时间: 2015
• 期刊: Journal of ophthalmology
• 影响因子: 1.9
• 作者: Zhang H;Dai X;Qi Y;He Y;Du W;Pang JJ
• 通讯作者: Pang JJ

Retinitis Pigmentosa: Disease Mechanisms, Diagnosis, and Therapies.

色素性视网膜炎：疾病机制、诊断和治疗。

• DOI: 10.1155/2015/819452
• 发表时间: 2015
• 期刊: Journal of ophthalmology
• 影响因子: 1.9
• 作者: Shu,Xinhua;Pang,Ji-Jing;Zhang,Houbin;Mansfield,David
• 通讯作者: Mansfield,David

AAV-mediated gene therapy in mouse models of recessive retinal degeneration.

• DOI: 10.2174/156652412799218877
• 发表时间: 2012-03
• 期刊: Current molecular medicine
• 影响因子: 2.5
• 作者: Pang JJ;Lei L;Dai X;Shi W;Liu X;Dinculescu A;McDowell JH
• 通讯作者: McDowell JH