siRNA Drugs for Genetic Disease Treatment
Context:
Researchers from Nagoya University in Japan have successfully modified siRNA using formamide to minimise off-target effects, enhancing the safety of siRNA-based genetic therapies.
More on News:
- A major source of off-target effects is a seven-nucleotide segment called the seed region, found within the guide strand of the siRNA.
- Region critical for target recognition, and off-target effects frequently occur because the seed region sequence forms base pairs with non-target mRNA strands.
Small interfering RNA (siRNA) are short, double-stranded RNAs that interact with the target’s messenger RNA (mRNA), hindering their expression. By silencing the products of harmful genes, such as disease-causing proteins, siRNAs offer potential treatments for a range of genetic diseases. However, the therapeutic potential of siRNAs is limited by off-target effects, which occur when siRNAs interact with non-target mRNA strands.
Key Highlights:
- The team used formamide to chemically modify siRNA, specifically targeting the seed region that interacts with mRNA.
- Formamide groups can inhibit the formation of hydrogen bonds, which are essential for the stability of the double helix in mRNA.
- By interfering with these hydrogen bonds, formamide destabilises the helical structure of the mRNA, causing denaturation or separation of the strands.
- This modification makes it difficult for the seed region of siRNA to bind to non-target mRNA, thereby reducing the risk of off-target effects.
- The formamide modification has been shown to suppress off-target effects more effectively than previous chemical modifications.
Applications and Implications:
- The improved siRNA drugs could potentially be used to treat genetic diseases such as hereditary transthyretin amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1, primary hypercholesterolemia, and mixed dyslipidemia.
- It allows for a more flexible siRNA design while achieving the desired suppression of unintended interactions.
Ribonucleic acid (RNA) is a nucleic acid found in all living cells, structurally similar to DNA but usually single-stranded. It has a backbone of alternating phosphate groups and ribose sugar, with bases adenine (A), uracil (U), cytosine (C), or guanine (G). Key types of RNA include messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). Some RNAs also regulate gene expression, and certain viruses use RNA as their genetic material.
- Genetic disorders are diseases caused by alterations in the DNA sequence, which can significantly impact an individual’s health. These disorders can be categorised based on how the mutations affect the genetic material.
Types of Genetic Disorders:
- Monogenic disorders are caused by mutations in a single gene, such as sickle cell disease and cystic fibrosis, and can be inherited in different patterns like autosomal dominant or recessive.
- Multifactorial inheritance disorders result from mutations in multiple genes combined with environmental factors, including heart disease and diabetes.
- Chromosomal disorders arise from changes in chromosome number or structure, like Down syndrome or Turner syndrome.
- Acquired genetic mutations occur during an individual’s life due to environmental factors or random errors, leading to conditions such as certain cancers.
