自放大mRNA 增强胚胎外胎mRNA的传递能力
Alex L Huang1, Emily M Scire1, Tanya T Dang1
1Department of Surgery, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
概括
自放大mRNA (saRNA) 显示优越的胎儿和新生儿分布,与线性mRNA相比,在胚胎内注射后. saRNA增强了蛋白质翻译,最大限度地提高了胎儿mRNA疗法的治疗潜力.
科学领域:
- 生物技术是生物技术.
- 分子生物学分子生物学
- 发育生物学 发展生物学
背景情况:
- 用于胎儿治疗的线性mRNA的内注射受到短半衰期和翻译的限制.
- 自放大mRNA (saRNA) 是为体内对感兴趣基因 (GOI) 的放大而设计的.
- 与传统的线性mRNA相比,saRNA提供了增强蛋白质表达的潜力.
研究的目的:
- 为了比较saRNA与线性mRNA的胎儿和新生儿分布和翻译.
- 在大鼠模型中评估通过内注射输送的saRNA的治疗潜力.
主要方法:
- 在Sprague-Dawley大鼠的怀孕第17天,给他们注射了包装在 lipopolyplex 的线性mRNA或编码火 luciferase 的saRNA.
- 对照组接受了 lipopolyplex 没有mRNA.
- 路西法酶活性在预产期和产后第7天和第14天被测量在多个胎儿和新生儿解剖部位.
主要成果:
- 与对照组相比,saRNA在9个解剖部位 (包括胎盘,肝脏,心脏和脏) 显示出显著更高的露西法酶活性.
- 线性mRNA仅在产后的带中显示出显著更高的活性.
- 在以后的时间点,mRNA组和对照组之间没有发现显著差异.
结论:
- 与线性mRNA相比,saRNA导致胎儿和新生儿在跨胚胎分娩后的蛋白质翻译更加强大和延长.
- saRNA对通过羊水传递的基于mRNA的胎儿疗法的疗效有显著的前景.
- 这项研究支持saRNA作为跨胎胎基因治疗应用的优越平台.
相关概念视频
01:59CRISPR
Genome editing technologies allow scientists to modify an organism’s DNA via the addition, removal, or rearrangement of genetic material at specific genomic locations. These types of techniques could potentially be used to cure genetic disorders such as hemophilia and sickle cell anemia. One popular and widely used DNA-editing research tool that could lead to safe and effective cures for genetic disorders is the CRISPR-Cas9 system. CRISPR-Cas9 stands for Clustered Regularly Interspaced Short...
01:38Fertilization
During fertilization, an egg and sperm cell fuse to create a new diploid structure. In humans, the process occurs once the egg has been released from the ovary, and travels into the fallopian tubes. The process requires several key steps: 1) sperm present in the genital tract must locate the egg; 2) once there, sperm need to release enzymes to help them burrow through the protective zona pellucida of the egg; and 3) the membranes of a single sperm cell and egg must fuse, with the sperm...
02:51mRNA Stability and Gene Expression
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
01:13Formation of Muscle Fibers from Myoblasts
De novo myogenesis, or the formation of muscle fibers, begins during the early embryonic stages. The skeletal muscle is formed from somites– blocks of embryonic cell layers. The somites are further divided into dermatomes, myotomes, sclerotomes, and syndetomes. Among these, the myotomes give rise to muscle fibers.
Muscle progenitor cells (MPCs) are formed from the myotomes. MPCs express genes that encode the transcription factors Pax3 and Pax7. Along with Pax 3/7, other transcription factors...
Muscle progenitor cells (MPCs) are formed from the myotomes. MPCs express genes that encode the transcription factors Pax3 and Pax7. Along with Pax 3/7, other transcription factors...
02:51mRNA Stability and Gene Expression
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
01:23Regulation of Expression at Multiple Steps
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...