用基因疗法瞄准疾病的驱动因素
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What is gene therapy?
Gene therapy is a relatively new type of treatment approach that has the potential to modify and even cure diseases by editing the genes responsible for causing illness.
有时在出生时，整个基因或其中一个基因的一部分缺失了. Other times, over the course of a lifespan, 曾经健康的基因会发生突变，变得有缺陷. Depending on the exact problem, 现在，利用基因疗法直接治疗疾病已经成为可能 repairing a gene in the genome or through delivering 一个缺失基因的额外拷贝来表达一种具有治疗作用的蛋白质.
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Our strategies in gene therapy are two-fold; we leverage CRISPR gene editing techniques to repair broken genes and use adeno-associated viruses (AAV) to deliver therapeutic proteins, new copies of genes, or biologic therapeutics – with the hope of providing long-term treatment for rare or chronic diseases.
What is CRISPR?
CRISPR是一种编辑生物体遗传物质的突破性方法. At its core, CRISPR acts as molecular scissors that can be used to precisely cut and modify a DNA sequence of interest. Accurate, programmable and adaptable, this technology has found widespread application across several areas of biological and biopharmaceutical research.
CRISPR系统包含两个组成部分:分子剪刀(一种酶), traditionally spCas9) and a guide RNA (gRNA) that ‘guides’ the enzyme to the part of the genome needing repair. In addition to using CRISPR for genetic therapies, we are exploring its potential to help create cell-based therapies.
CRISPR是过去十年中最令人兴奋的生命科学发现. 它使澳门第一赌城在线娱乐能够识别和验证药物发现的新靶点, and as a medicine allows us to edit genes to enable the treatment and hopefully cure of many genetic diseases.
Building our CRISPR tool-box
Over the last several years, we have successfully begun to build our CRISPR toolbox – a range of innovative tools such as CRISPR GUARD,1 CRISPR VIVO2 and DISCOVER-Seq.3 These tools help establish how CRISPR can be used as a precise and effective gene therapy in the clinic.
More recently, our CRISPR toolbox has grown with the addition of three new tools and technologies that have the potential to further improve the efficacy and precision of CRISPR-based medicines: Prime Editor nuclease (PEn) technology, 2iHDR, and SpOT-ON (PsCas9).
Prime Editor nuclease (PEn)
In 2022, our scientists developed Prime Editor nuclease (PEn) technology that can efficiently introduce precise genetic insertions through multiple double-stranded DNA repair pathways. 除了提高生成插入的效率之外, 使用PEn编辑可以减少不必要的大删除, 减少脱靶效果的频率. 这种新的基因编辑方法驱动高效的基因插入, 减少不必要编辑的风险, 推进治疗用途的潜力.4
2iHDR
澳门第一赌城在线娱乐的科学家开发了一种名为2iHDR的策略, which aims to improve the success of gene editing by suppressing two pathways of gene repair – called non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) – that can lead to imprecise gene editing. 使用两种抑制剂的组合, we can dramatically improve the efficiency of CRISPR gene editing while reducing the risk of off-target effects. 这种策略对细胞治疗和基因治疗都有很大的前景.5
SpOT-ON
We are constantly striving to improve our CRISPR technology for the treatment and potential cure of genetic conditions. To this end, 澳门第一赌城在线娱乐的科学家已经开发出一种利用工程酶的增强型CRISPR系统, SpOT-ON. 这种酶切割DNA的效率与传统酶相似, SpCas9, 对基因组中目标位点的特异性增强. 在高胆固醇血症的概念验证临床前研究中, SpOT-ON成功靶向了PCSK9基因, 导致血浆中相关PCSK9蛋白水平降低. 这项最近的研究强调了CRISPR中越来越多的安全特性, 使其更适合治疗应用，并应用这些 in vivo for the first time.6
By altering DNA repair pathways with 2iHDR and harnessing a highly specific Cas9 variant with SpOT-ON, 澳门第一赌城在线娱乐可以以更高的精度和效率实现有针对性的基因修饰, 推动该领域的进一步发展.
什么是腺相关病毒(aav)?
Adeno-associated viruses (AAVs) are naturally occurring viruses that are able to enter many different cell types in the body. Importantly, AAVs do not act like a typical virus as they do not replicate and do not cause disease. All viruses, including AAVs, 高度专门化，将遗传物质引入细胞, 使它们成为基因治疗的理想选择. Therefore, we can modify AAVs with the ambition to provide long-term benefits to people living with rare and chronic diseases.
澳门第一赌城在线娱乐修改aav的主要方法有两种:
The DNA within an AAV can be engineered to replace its viral genetic material with DNA sequences that encode healthy human genes or other molecules. These other molecules could be a therapeutic protein that is not normally expressed in the body, such as an antibody medicine. Alternatively, synthetic forms of healthy genes can be delivered to compensate for the presence of a defective copy present in a genetic disease.
AAVs can deliver CRISPR gene editing components that then work to correct a person’s own genes.
We can guide AAVs to deliver genes to specific target cells by modifying the outer surface – called the capsid – to improve its delivery properties. 通过增加对目标细胞的选择性，避开其他细胞, 澳门第一赌城在线娱乐可以优化安全性和有效性.
在澳门第一赌城在线娱乐的治疗方案中，澳门第一赌城在线娱乐正在开发针对肝脏的新型aav, as well as building our capabilities internally and with collaborators to use AAVs to treat disease in other organs such as heart, lung, muscle and brain.
共同推进基因治疗
Join us
We welcome committed, talented scientists to join us as we develop new medicines that have the potential to deliver healthcare experiences and outcomes that enable people to enjoy fulfilling lives. We are well-positioned to develop cutting-edge gene therapies to address a range of genetic diseases associated with significant unmet need. 通过为澳门第一赌城在线娱乐的员工提供资源和支持来推动科学的发展, 澳门第一赌城在线娱乐正在超越平凡，帮助改善世界各地患者的生活.
We are proud of our progress, 为未来的挑战做好准备, and confident that gene therapies will help improve the outlook for patients with some of today’s most serious and life limiting diseases.
Collaborating for success
We partner with academia, governments, peer companies, biotechs, 科学组织和患者团体获得最好的科学. 澳门第一赌城在线娱乐的承诺创造强大, long-term partnerships helps enable us to speed the delivery of innovative and life-changing medicines to the people who need them most.
References
1. Coelho, M.A., De Braekeleer, E., Firth, M. et al. CRISPR GUARD使用短向导rna保护脱靶位点免受Cas9核酸酶活性的影响. Nat Commun 11, 4132 (2020). http://doi.org/10.1038/s41467-020-17952-5.
2. Akcakaya, Pinar, Maggie L. Bobbin, Jimmy A. 郭，Jose Malagon-Lopez, Kendell Clement, Sara P. Garcia, Mick D. Fellows, et al. 2018. 没有可检测的全基因组脱靶突变的体内CRISPR编辑.” Nature 561 (7723): 416–19.
3. Wienert, Beeke, Stacia K. Wyman, Christopher D. Richardson, Charles D. Yeh, Pinar Akcakaya, Michelle J. Porritt, Michaela Morlock, et al. 2019. 使用DISCOVER-Seq在体内无偏检测CRISPR脱靶.” Science 364 (6437): 286–89.
4. Peterka M, Akrap N, Li S, Wimberger S，等. 利用DSB修复促进高效同源依赖和独立的引物编辑. Nature Communications 2022; March 24th
5. 温伯格S, Akrap N, Firth M，等. Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing. Nat Commun. 2023;14(1):4761. Published 2023 Aug 14. doi:10.1038/s41467-023-40344-4
6. Bestas, B., Wimberger, S., Degtev, D. et al. A Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo. Nat Commun 14, 5474 (2023). http://doi.org/10.1038/s41467-023-41240-7
Veeva ID: Z4-54364
筹备日期:2023年9月