What a great Idea👍🏻
Acga Cheng et al. Int J Mol Sci. 2022.Show details Abstract PubMed PMID Full text linksCite
Abstract
The understanding of how genetic information may be inherited through generations was established by Gregor Mendel in the 1860s when he developed the fundamental principles of inheritance. The science of genetics, however, began to flourish only during the mid-1940s when DNA was identified as the carrier of genetic information. The world has since then witnessed rapid development of genetic technologies, with the latest being genome-editing tools, which have revolutionized fields from medicine to agriculture. This review walks through the historical timeline of genetics research and deliberates how this discipline might furnish a sustainable future for humanity.
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Keywords: agriculture; biodiversity; gene-editing; genetic technologies; heredity; medicine; sustainability.
Evolution of genetic techniques: past, present, and beyond
https://journals.asm.org/doi/10.1128/msphere.00095-24
https://pubmed.ncbi.nlm.nih.gov/25874212/
Genetics is the study of heredity, which means the study of genes and factors related to all aspects of genes. The scientific history of genetics began with the works of Gregor Mendel in the mid-19th century. Prior to Mendel, genetics was primarily theoretical whilst, after Mendel, the science of genetics was broadened to include experimental genetics. Developments in all fields of genetics and genetic technology in the first half of the 20th century provided a basis for the later developments. In the second half of the 20th century, the molecular background of genetics has become more understandable. Rapid technological advancements, followed by the completion of Human Genome Project, have contributed a great deal to the knowledge of genetic factors and their impact on human life and diseases. Currently, more than 1800 disease genes have been identified, more than 2000 genetic tests have become available, and in conjunction with this at least 350 biotechnology-based products have been released onto the market. Novel technologies, particularly next generation sequencing, have dramatically accelerated the pace of biological research, while at the same time increasing expectations. In this paper, a brief summary of genetic history with short explanations of most popular genetic techniques is given.
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RNA-based therapeutics: an overview and prospectus
The growing understanding of RNA functions and their crucial roles in diseases promotes the application of various RNAs to selectively function on hitherto „undruggable“ proteins, transcripts and genes, thus potentially broadening the therapeutic targets. Several RNA-based medications have been approved for clinical use, while others are still under investigation or preclinical trials. Various techniques have been explored to promote RNA intracellular trafficking and metabolic stability, despite significant challenges in developing RNA-based therapeutics. In this review, the mechanisms of action, challenges, solutions, and clinical application of RNA-based therapeutics have been comprehensively summarized.
An overview of major developments in the RNA-targeting field.
A timeline of RNA-based technological advances, drug approvals and other important events are highlighted. Rapid development in the RNA-targeting field has been applied to treat rare and common diseases. ASOs antisense oligonucleotides, RNAi RNA interference, RISC RNA-induced silencing complex, siRNA small interfering RNA, saRNA small activating RNAs, ssRNA single-stranded RNA.
Types of RNA-based therapeutics and modes of action.
A Antisense oligonucleotides (ASOs) can modulate the target gene expression through two mechanisms. (①) In the occupancy-mediated degradation way, ASOs trigger the target mRNA cleavage by RNase H1 or ribozymes. The Occupancy-only mechanisms do not directly degrade target RNA. Instead, it regulates the gene expression in several ways: (②) alter RNA splicing using splice-switching ASOs to induce exon skipping or exon inclusion; (③) lead to nonsense-mediated mRNA decay (NMD); (④) inhibit or activate translation; (⑤) block the microRNAs binding to target mRNA. B RNA interference (RNAi). Long double-stranded RNA (dsRNA) and precursor microRNA (pre-miRNA) are processed by Dicer into short interfering RNA (siRNA). The antisense strand (indicated as a blue strand) of siRNA is loaded into the RNA-induced silencing complex (RISC) for RNA targeting, degradation or translation repression. CCRISPR/Cas-based RNA editing system includes two Cas nuclease categories, Cas9 and Cas13. A guide RNA(gRNA) binds to Cas9 to cleave ssRNA with (①) or without (②) the help of a protospacer-adjacent motif (PAM). (③) A single CRISPR RNA (crRNA) guides Cas13 to target specific RNA having a protospacer flanking sequence (PFS). (④) In addition to knockdown target RNA, a catalytically deactivated Cas13b (dCas9b) facilitates the A-to-I editing with ADAR. D RNA aptamers function as agonizts or delivery agents. (①) As an antagonist aptamer, Pegaptanib interacts explicitly with vascular endothelial growth factor (VEGF) to inhibit the interaction of VEGF with its receptors, thus treating macular degeneration. (②) Cell type-specific RNA aptamers deliver agents (miRNA, siRNA, shRNA, antibody and chemotherapy drugs) by linking to or conjugating. E mRNA vaccine. (①) The mRNA vaccine against SARS-CoV-2 (mRNA-1273) is delivered into antigen-presenting cells by lipid nanoparticle (LNP). (②)The mRNA encoding SARS-CoV-2 spike protein is released into the cytoplasm and translated to antigen protein by the ribosome. (③) Some antigen proteins are degraded into small peptides by the proteasome and presented to the surface of CD8+ T cells by major histocompatibility complex I (MHCI). The CD8+ cytotoxic T-cell-mediated immunity kills infected cells by secreting perforin or granzyme. (④) Other antigen proteins are degraded in the lysosome and displayed on the surface of T helper cells by MHC II. The B-cell/antibody-mediated humoral immunity uses antibodies to neutralize pathogens.
Overcoming challenges in the development of RNA therapeutics.
A Common chemical modifications. RNA-based drugs often have various chemical modifications, including 5′-and 3′-end conjugates, 2′-sugar substitution and internucleoside linkage modifications. B Nanocarriers delivery strategies. Five representative nanocarriers are shown: (①) Lipid nanoparticles encapsulating nucleic acids. (②) Cationic polymers electrostatically bind to negatively-charged nucleic acids to form polyplexes. (③) Engineered exosomes with aptamers or therapeutic RNAs on the outer surface. (④) Spherical nucleic acid nanoparticle consisting of an inorganic core coated in densely packed oligonucleotides attached by chemical linkages. (⑤) Self-assembled DNA cage tetrahedron nanostructure. Oligonucleotide drugs can be incorporated into the design of the DNA cage itself. Additional targeting ligands and polyethylene glycol (PEG) can be further conjugated to the nanostructure. These nanocarriers can deliver RNA molecules through binding to the cell membrane, endocytosis, endosome escape and RNAs are released in the cytoplasm and translation to proteins or incorporated into corresponding ribonucleoprotein complexes to silence target transcripts.
Molecular mechanisms of RNA-triggered gene silencing machineries
Zhonghan Li et al. Acc Chem Res. 2012.Free PMC articleShow details Abstract PubMed PMID Full text linksCite
Abstract
Gene silencing by RNA triggers is an ancient, evolutionarily conserved, and widespread phenomenon. This process, known as RNA interference (RNAi), occurs when double-stranded RNA helices induce cleavage of their complementary mRNAs. Because these RNA molecules can be introduced exogenously as small interfering RNAs (siRNAs), RNAi has become an everyday experimental tool in laboratory research. In addition, the number of RNA-based therapeutics that are currently in clinical trials for a variety of human diseases demonstrate the therapeutic potential of RNAi. In this Account, we focus on our current understanding of the structure and function of various classes of RNAi triggers and how this knowledge has contributed to our understanding of the biogenesis and catalytic functions of siRNA and microRNA in mammalian cells. Mechanistic studies to understand the structure and function of small RNAs that induce RNAi have illuminated broad functions of the ancient RNAi machinery in animals and plants. In addition, such studies have provided insight to identify endogenous physiological gene silencing RNA triggers that engage functional machineries similar to siRNAs. Several endogenous small RNA species have been identified: small noncoding RNAs (microRNAs), piwi-interacting RNAs (piRNAs), and endogenous siRNAs (endo-siRNAs). microRNAs are the most widespread class of small RNAs in mammalian cells. Despite their importance in biology and medicine, the molecular and cellular mechanisms of microRNA biogenesis and function are not fully understood. We provide an overview of the current understanding of how these molecules are synthesized within cells and how they act on gene targets. Interesting questions remain both for understanding the effects of modifications and editing on microRNAs and the interactions between microRNAs and other cellular RNAs such as long noncoding RNAs.
Figures
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Figure 1
Steps in RISC function. Double-stranded…
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Crystal Structure of T. thermophilus…
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Kinetics of RISC assembly and…
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Canonical and noncanonical microRNA biogenesis…
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microRNA function. After loading with…
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