Made of components found in the human body, the programmable system is a step toward safer, targeted delivery of gene editing and other molecular therapeutics.
該由人體中發現之成分製成的可編程序系統，是邁向更安全、鎖定之遞送基因編輯及其他分子療法的一步。
Researchers from MIT, the McGovern Institute for Brain Research at MIT, the Howard Hughes Medical Institute, and the Broad Institute of MIT and Harvard have developed a new way to deliver molecular therapies to cells. The system, called SEND, can be programmed to encapsulate and deliver different RNA cargoes.
來自美國麻省理工學院、麻省理工學院麥戈文腦研究所、霍華德休斯醫學研究所及麻省理工學院暨哈佛大學博德研究所的研究人員們，已經研發出一種，將分子療法遞送到細胞的新方法。該被稱為SEND的系統能被編製程序，來封裝及遞送不同的RNA裝載物。
SEND harnesses natural proteins in the body that form virus-like particles and bind RNA, and it may provoke less of an immune response than other delivery approaches.
SEND利用於人體內，形成類似病毒之粒子，並與RNA結合的天然蛋白質。因此，該系統能誘發比其他遞送方法，較少的免疫反應。
The new delivery platform works efficiently in cell models, and, with further development, could open up a new class of delivery methods for a wide range of molecular medicines — including those for gene editing and gene replacement.
在諸多細胞模型中，該新的遞送平台有效地運作。因此，隨著進一步的發展，可能為廣泛的分子藥物開啓一種，包括用於基因編輯及基因替換的新類型遞送方法。
Existing delivery vehicles for these therapeutics can be inefficient and randomly integrate into the genome of cells, and some can stimulate unwanted immune reactions. SEND has the promise to overcome these limitations, which could open up new opportunities to deploy molecular medicine.
就上述治療法而言，現有遞送載體會是效率低下，且隨機整合到細胞的基因體中，結果有些會刺激不需要的免疫反應。SEND具有克服此些缺陷的指望，這可能開啓部署分子醫學的新機會。
“The biomedical community has been developing powerful molecular therapeutics, but delivering them to cells in a precise and efficient way is challenging,” said CRISPR pioneer Feng Zhang, senior author on the study, core institute member at the Broad Institute, investigator at the McGovern Institute, and the James and Patricia Poitras Professor of Neuroscience at MIT.
群集之規律性間隔開的短迴文結構複製(CRISPR：Clustered Regularly Interspaced Short Palindromic Repeat)先驅，Feng Zhang(該項研究資深撰文人、博德研究所核心成員、麥戈文研究所調查研究員及麻省理工學院詹姆斯暨帕特里夏•波伊特拉斯神經科學教授)宣稱：「生物醫學界一直在開發，效力大的分子療法，不過以精確、有效的方式，將它們遞送到細胞中，深具挑戰性。」
“SEND has the potential to overcome these challenges.” Zhang is also an investigator at the Howard Hughes Medical Institute and a professor in MIT’s Departments of Brain and Cognitive Sciences and Biological Engineering.
也是霍華德休斯醫學研究所之調查研究員，及麻省理工學院腦暨認知科學與生物工程系教授的Zhang宣稱：「SEND具有克服此些挑戰的潛力。」
Reporting in Science, the team describes how SEND (Selective Endogenous eNcapsidation for cellular Delivery) takes advantage of molecules made by human cells. At the center of SEND is a protein called PEG10, which normally binds to its own mRNA and forms a spherical protective capsule around it.
於《科學》期刊的報導中，該團隊記述了，SEND(用於細胞遞送的選擇性內源蛋白膜包裹)如何利用人類細胞製造的分子。於SEND的中心是一種，被稱為PEG10的蛋白質。該蛋白質通常與其自身的mRNA結合，並在其周遭形成一個，球狀的保護性膜囊。
In their study, the team engineered PEG10 to selectively package and deliver other RNA. The scientists used SEND to deliver the CRISPR-Cas9 gene editing system to mouse and human cells to edit targeted genes.
在他們的研究中，該團隊設計了，選擇性封包及遞送其他RNA的PEG10。科學家們使用了SEND，來將CRISPR-Cas9的基因編輯系統，遞送到小鼠及人類細胞，以編輯鎖定的基因。(CRISPR- Cas9：Cas9(CRISPR associated protein 9：是一種在某些細菌對DNA病毒之免疫防禦中，起至關重要作用的蛋白質)群集之規律性間隔開的短迴文結構複製)
First author Michael Segel, a postdoctoral researcher in Zhang’s lab, and Blake Lash, second author and a graduate student in the lab, said PEG10 is not unique in its ability to transfer RNA.
首要撰文人，Zhang實驗室的博士後研究員，Michael Segel及次要撰文人，該實驗室研究生Blake Lash表示，PEG10其能耐並非唯獨轉移RNA。
“That's what’s so exciting,” said Segel. “This study shows that there are probably other RNA transfer systems in the human body that can also be harnessed for therapeutic purposes. It also raises some really fascinating questions about what the natural roles of these proteins might be.”
Segel宣稱：「那是很令人振奮的事。就治療的目的而言，該項研究顯示，人體中可能具有，也能被利用的其他RNA轉移系統。這也引發了一些有關，此些蛋白質自然角色，會是什麼之非常引人矚目的問題。」
The PEG10 protein exists naturally in humans and is derived from a “retrotransposon” — a virus-like genetic element — that integrated itself into the genome of human ancestors millions of years ago. Over time, PEG10 has been co-opted by the body to become part of the repertoire of proteins important for life.
天然存在於人類中的PEG10蛋白質，源自數百萬年前，自身整合到人類祖先之基因體中的一種“逆轉錄轉座子”(一種類似病毒的遺傳物質)。隨著時間推移，PEG10已經被身體吸收，成為對生命很重要之蛋白質庫的一部分。
Four years ago, researchers showed that another retrotransposon-derived protein, ARC, forms virus-like structures and is involved in transferring RNA between cells. Although these studies suggested that it might be possible to engineer retrotransposon proteins as a delivery platform, scientists had not successfully harnessed these proteins to package and deliver specific RNA cargoes in mammalian cells.
四年前，研究人員們證實，另一種源自逆轉錄轉座子的蛋白質，ARC形成類似病毒的結構且涉及了，於細胞間轉移RNA。雖然些研究暗示，或許可能設計出逆轉錄轉座子蛋白質，作為一種遞送平台。不過，科學家們未曾成功利用此些蛋白質，在哺乳動物細胞中，封包及遞送特定RNA裝載物。
Knowing that some retrotransposon-derived proteins are able to bind and package molecular cargo, Zhang’s team turned to these proteins as possible delivery vehicles. They systematically searched through these proteins in the human genome for ones that could form protective capsules.
知曉一些源自逆轉錄轉座子之蛋白質，能結合及封包分子裝載物。Zhang的團隊轉向此些蛋白質，作為可能的遞送載體。他們有系統地搜尋了，人類基因體中的此些蛋白質，以找尋可能形成保護性膜囊的蛋白質。
In their initial analysis, the team found 48 human genes encoding proteins that might have that ability. Of these, 19 candidate proteins were present in both mice and humans.
在他們的初步分析中，該團隊發現了48個，可能具有那種能耐之編碼蛋白質的人類基因。其中，19種候選蛋白質存在於小鼠及人類中。
In the cell line the team studied, PEG10 stood out as an efficient shuttle; the cells released significantly more PEG10 particles than any other protein tested. The PEG10 particles also mostly contained their own mRNA, suggesting that PEG10 might be able to package specific RNA molecules.
在該團隊研究的細胞種系中，PEG10突出如同一種有效率的梭子。此些細胞比任何其他經測試的蛋白質，顯著釋放出更多的PEG10粒子。此些PEG10 粒子，多半也具有自身的mRNA。這暗示，PEG10或許能封包特定的RNA分子。
To develop the SEND technology, the team identified the molecular sequences, or “signals,” in PEG10’s mRNA that PEG10 recognizes and uses to package its mRNA. The researchers then used these signals to engineer both PEG10 and other RNA cargo so that PEG10 could selectively package those RNAs.
為了開發SEND技術，該團隊確認了，於PEG10之mRNA中，PEG10識別及用來封包其mRNA的分子序列，也就是“信號”。之後，此些研究人員使用了此些信號，來設計PEG10及其他RNA裝載物，以便PEG10能選擇性地封包那些RNA。
Next, the team decorated the PEG10 capsules with additional proteins, called “fusogens,” that are found on the surface of cells and help them fuse together.
接下來，該團隊使用，在細胞表面被發現且有助於它們融合在一起，被稱為“融合素”的額外蛋白質，修飾了PEG10膜囊。
By engineering the fusogens on the PEG10 capsules, researchers should be able to target the capsule to a particular kind of cell, tissue, or organ. As a first step towards this goal, the team used two different fusogens, including one found in the human body, to enable delivery of SEND cargo.
藉由在PEG10膜囊上，設計此些融合素。研究人員們應該能將這種膜囊，鎖定於特定類型的細胞、組織或器官。作為邁向此目標的第一步，該團隊使用了兩種不同的融合素，包括一種在人體中發現的融合素，以使能遞送SEND裝載物。
“By mixing and matching different components in the SEND system, we believe that it will provide a modular platform for developing therapeutics for different diseases,” said Zhang.
Zhang宣稱：「在SEND系統中，藉由混合及匹配不同的成分。他們認為，這能提供一種，為不同疾病開發療法的模組式平台。」
SEND is composed of proteins that are produced naturally in the body, which means it may not trigger an immune response. If this is demonstrated in further studies, the researchers say SEND could open up opportunities to deliver gene therapies repeatedly with minimal side effects.
SEND是由體內自然產生的蛋白質組成。這意味著，其不可能觸發免疫反應。此些研究人員表示，倘若這在進一步的研究中被證實，SEND可能開啟，以最小副作用重複遞送基因療法的機會。
“The SEND technology will complement viral delivery vectors and lipid nanoparticles to further expand the toolbox of ways to deliver gene and editing therapies to cells,” said Lash.
Lash宣稱：「這種SEND技術將補充，病毒遞送載體及脂質奈米粒子，來進一步擴大，將基因及編輯療法遞送到細胞的方法工具箱。」
Next, the team will test SEND in animals and further engineer the system to deliver cargo to a variety of tissues and cells. They will also continue to probe the natural diversity of these systems in the human body to identify other components that can be added to the SEND platform.
接下來，該團隊將在動物身上測試SEND，並進一步設計該系統，來將裝載物遞送到各種組織及細胞。他們也將持續探索此些系統，在人體中的自然多樣性，以確認能被添加到SEND平台的其他成分。
“We’re excited to keep pushing this approach forward,” said Zhang. “The realization that we can use PEG10, and most likely other proteins, to engineer a delivery pathway in the human body to package and deliver new RNA and other potential therapies is a really powerful concept.”
Zhang宣稱：「繼續向前推動此種方法，他們是振奮的。認知到，能使用PEG10及最有可能的其他蛋白質，來設計人體中，封包及遞送新RNA與其他潛在療法的遞送途徑，是一種非常強有力的概念。」
網址：https://news.mit.edu/2021/send-peg10-drug-delivery-0819
翻譯: 許東榮
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