Defining Barriers to Gene Therapy

定义基因治疗的障碍

基本信息

批准号：
10659287
负责人：
Stephen H Tsang
金额：
$ 33.21万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659287
关键词：
Address Adult Affect Age Alleles Amblyopia American Behavior Cations Cessation of life Clinical Clinical Trials Cone Cone dystrophy Cre driver DNA cassette Degenerative Disorder Development Diagnosis Disease Engineering Enrollment Functional disorder Funding GTP-Binding Proteins Gene therapy trial Genes Genetic Genotype Goals Human Interruption Intervention LoxP-flanked allele Mediating Metabolic Modeling Mus Mutation Nuclear Onset of illness Pathologic Pathway interactions Patients Phenotype Photoreceptors Pre-Clinical Model Production Protocols documentation Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Rod System Tamoxifen Testing Therapeutic Therapeutic Intervention Time Translating Vertebrate Photoreceptors Viral Vector Vision Visual aerobic glycolysis alpha Subunit Transducin anaerobic glycolysis arrestin3 brain circuitry clinically relevant clinically significant critical period cyclic nucleotide-gated cation channel effective therapy gene therapy guanine nucleotide binding protein improved inducible Cre mouse model novel phosphodiesterase 6 phosphoric diester hydrolase photoreceptor degeneration preservation promoter research study resilience restoration synaptogenesis visual dysfunction visual threshold

项目摘要

PROJECT SUMMARY Of the retinal degenerative diseases that affect 9 million Americans, rod and cone photoreceptor dystrophies are arguably the most devastating. Gene therapy is a potential means to strengthen photoreceptor viability. However, the first human gene therapy trial for retinal degeneration found improved visual function but did not slow degeneration of photoreceptors. The goal of this gene therapy-oriented proposal is to determine whether therapy is achievable in the context of an already diseased retina and at what timepoints gene therapy should be administered in order to improve functional vision in rod and cone dystrophies. During the previous funding period, we succeeded in restoring retinal function in mouse model of rod degeneration, demonstrating that only 12% of resilient photoreceptors are needed for rescue. We now intend to determine if this threshold may be shifted to an even lower number of resilient photoreceptors (6%) for functional vision. We will also determine whether cone-specific rescue is possible at late stages of disease. Finally, we will determine the latest timepoint at which gene therapy can be administered for rod monochromatism. To do this, we will use a novel, inducible genetic rescue system in the cone-specific G-protein, guanine nucleotide binding α- transducin 2 (Gnat2), which will allow us to conditionally reverse GNAT2-deficiency while controlling the temporal and spatial aspects of phenotypic reversal. We will also use a phosphodiesterase 6 (Pde6) mouse as a model for rod dystrophy. The Gnat2floxSTOP/ Gnat2floxSTOP::Arr3CreERT2/WT and Pde6floxSTOP/PdefloxSTOP::Arr3CreERT2/WT programmable models will provide a platform for contributing to ongoing efforts aimed at increasing restoration of visual function following gene therapy for rod- and cone-mediated dystrophies. They will also allow us to address several compelling, clinically relevant questions: Is the brain’s circuitry sufficiently plastic to recover from the pathological changes caused by the Gnat2 mutation? Is there a point of no return after which, despite reversion of the genotype to wild type, cones cannot be salvaged? Can temporal barriers to gene therapy be relieved by metabolic reprogramming? Taken together, this proposal is certain to 1) define the factors limiting interventional therapy; 2) validate a new, inducible models of rod- and cone-mediated retinal degeneration; and 3) determine whether metabolic reprogramming can serve as an efficacious, non-gene-specific strategy for treating retinal degeneration.

项目摘要影响900万美国人，杆和锥形感受器功能障碍的视网膜退行性疾病可以说是最毁灭性的。基因治疗是增强感光活性的潜在手段。然而，第一个永久性变性的人类基因疗法试验发现了视觉功能的改善，但没有光感受器的缓慢变性。该基因疗法的建议的目的是确定是否是否在已经剖析的视网膜的背景下可以实现治疗，并且在什么时间点基因治疗应进行为了改善杆和锥体营养不良的功能视觉而进行管理。在上一个资金期间，我们成功地恢复了Rod鼠标模型中的残留功能退化，表明仅需要12％的弹性感光体进行救援。我们现在打算确定该阈值是否可以转移到功能性较低的弹性光感受器（6％）想象。我们还将确定在疾病后期是否可以进行锥体特异性救援。最后，我们会的确定可以为杆单色疗法施用基因治疗的最新时间点。为此，我们将在锥体特异性的G蛋白鸟嘌呤核苷酸结合α-中使用新型的，可诱导的遗传救援系统跨多霉素2（GNAT2），这将使我们能够在控制临时性的同时有条件地逆转GNAT2缺乏效率和表型逆转的空间方面。我们还将使用磷酸二酯酶6（PDE6）小鼠作为模型杆营养不良。 gnat2floxstop/gnat2floxstop :: arr3creert2/wt and pde6floxstop/pdefloxstop :: arr3creert2/wt可编程模型将提供一个平台，以促进正在进行的努力，以增加视觉功能的恢复杆和锥介导的营养不良的基因治疗。他们还将允许我们解决一些引人注目的问题，临床上相关的问题：大脑的电路是否足以从病理变化中恢复由GNAT2突变引起？有没有回报的点，之后，目的地的基因型反向野生型，不能挽救锥体？代谢可以缓解基因疗法的暂时障碍重新编程？综上所述，该提议可以肯定地1）定义限制介入疗法的因素； 2）验证一个新的杆和锥介导的残留变性的诱导模型； 3）确定是否代谢重编程可以作为治疗永久性变性的有效，非基因的特定策略。

项目成果

期刊论文数量（60）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.

DOI：
10.1371/journal.pgen.1004688
发表时间：
2014-10
期刊：
PLoS genetics
影响因子：
4.5
作者：
Chen J;Ingham N;Kelly J;Jadeja S;Goulding D;Pass J;Mahajan VB;Tsang SH;Nijnik A;Jackson IJ;White JK;Forge A;Jagger D;Steel KP
通讯作者：
Steel KP

Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.

移植重新编程的胚胎干细胞可改善视网膜色素变性小鼠模型的视觉功能。

DOI：
10.1097/tp.0b013e3181d45a61
发表时间：
2010
期刊：
Transplantation
影响因子：
6.2
作者：
Wang,Nan-Kai;Tosi,Joaquin;Kasanuki,JenniferMie;Chou,ChaiLin;Kong,Jian;Parmalee,Nancy;Wert,KatherineJ;Allikmets,Rando;Lai,Chi-Chun;Chien,Chung-Liang;Nagasaki,Takayuki;Lin,Chyuan-Sheng;Tsang,StephenH
通讯作者：
Tsang,StephenH

Rapid and noninvasive imaging of retinal ganglion cells in live mouse models of glaucoma.

DOI：
10.1007/s11307-009-0292-2
发表时间：
2010-08
期刊：
MOLECULAR IMAGING AND BIOLOGY
影响因子：
3.1
作者：
Tosi, Joaquin;Wang, Nan-Kai;Zhao, Jin;Chou, Chai Lin;Kasanuki, J. Mie;Tsang, Stephen H.;Nagasaki, Takayuki
通讯作者：
Nagasaki, Takayuki

Allelic and phenotypic heterogeneity in ABCA4 mutations.