PhotoMorph3 and PhotoPS3 - Novel Light-Activated Antisense Agents

描述(申请人提供)：利用靶向光激活反义分子对基因表达的时空调节有望在透明模式生物中产生重要影响，在透明模式生物中，辐射可以在视觉上特定地针对已知的解剖地标。照射器官内选定的细胞允许特定基因在生物体发育过程中的任何时候以细胞级的分辨率被关闭，从而允许对特定基因在整个生物体中的作用进行深入的时空理解。这也允许研究在早期发育中必不可少的基因，否则就会导致致命的表型。我们开发了一个用于进行时空基因控制实验的商用试剂、软件和仪器平台。利用这些初步的成功，我们现在的目标是进一步开发和商业化新一代可光激活的反义试剂(PhotoMorph3.0“和PhotoPS3.0”)。所提出的光活化反义试剂是基于吗啉或硫代磷酸齐聚物，这些低聚物通过其外环氢键供体和受体受到保护，并带有可光化的笼状基团，破坏Watson-Crick与目标mRNA的配对。光照射裂解笼状基团，释放碱基参与与靶标的杂交。我们假设，外环碱基保护将提供比其他光活化形式更重要的优势，包括使用自动化的“紧密”关闭状态和方便的按需访问。这一阶段的SBIR的目标是使可光激活的反义化学用于商业规模的合成和实施。第二阶段SBIR的目标将是为各种发育途径(如GUT400、CNS500)开发经过验证的、交钥匙的“工具包”，其中将描述每种可光激活反义试剂的基本表型，并在公共数据库中为研究人员提供。 与公共健康相关：利用定向光激活分子来调节不同时间和不同地点的基因表达，有望对透明模式生物产生重要影响，在这种模式生物中，辐射可以在视觉上特定地瞄准已知的解剖地标。照射器官内选定的细胞允许特定基因在生物体发育过程中的任何时候以细胞级的分辨率被关闭，从而使人们能够深入了解特定基因在整个生物体不同位置和在其发育过程中的不同时间所起的作用。我们现在的目标是进一步开发新一代可光激活的化学品并将其商业化(PhotoMorph3.0“和PhotoPS3.0”)，我们相信这些化学品将提供比其他产品更重要的优势。

DESCRIPTION (provided by applicant): The spatiotemporal modulation of gene expression using targeted light to activate antisense molecules promises to have an important impact in transparent model organisms, where irradiation can be specifically targeted visually to known anatomic landmarks. Irradiating selected cells within organs permits specific genes to be turned off at any time during the development of the organism with cell-scale resolution, thereby permitting an in depth spatiotemporal understanding of the role of particular genes in the whole organism. This also allows the study of genes essential in early development that otherwise result in a lethal phenotype. We have developed a commercial reagent, software and instrumentation platform for conducting spatiotemporal gene-control experiments. Leveraging off these initial successes, we now aim to further develop and commercialize a new generation of photoactivatable antisense reagents (PhotoMorph3.0" and PhotoPS3.0"). The proposed photoactivatable antisense reagents are based on morpholino or phosphorthioate oligomers that are protected on their exocyclic hydrogen bond donors and acceptors with photolabile caging groups that disrupt Watson-Crick pairing with a target mRNA. Light irradiation cleaves the caging groups, freeing the bases to participate in hybridization with the target. We hypothesize that exocyclic base protection will offer important advantages over other photoactivatable formats, including a 'tight' off-state and facile on-demand access using automation. The goal of this Phase I SBIR is to make the photoactivatable antisense chemistry robust for commercial-scale synthesis and implementation. The goal of the Phase II SBIR will be to develop validated and turn-key "tool-kits" for various developmental pathways (e.g. gut400, CNS500), where the basic phenotype of each photoactivatable antisense reagent will be described and made available in a public database for researchers. PUBLIC HEALTH RELEVANCE: The modulation of gene expression at different times and locations using targeted light to activate molecules promises to have an important impact in transparent model organisms, where irradiation can be specifically targeted visually to known anatomic landmarks. Irradiating selected cells within organs permits specific genes to be turned off at any time during the development of the organism with cell-scale resolution, thereby permitting an in depth understanding of the role of particular genes in different locations in the whole organism and at different times during its development. We now aim to further develop and commercialize a new generation of photoactivatable chemicals for doing this (PhotoMorph3.0" and PhotoPS3.0") that we believe will offer important advantages over others.