Gene Silencing Therapy

Context

Scientists are exploring gene silencing therapy as a potential treatment for Hepatitis B, a viral infection that primarily affects liver cells (hepatocytes). An experimental therapy, CRMA-1001, developed by nChroma Bio, uses epigenetic mechanisms to suppress the activity of Hepatitis B viral genes. This development highlights the growing role of gene silencing in modern medicine.

Gene Silencing

1. Gene silencing is a process through which the expression of a particular gene is reduced or switched off.
2. It prevents or reduces the production of proteins associated with that gene.
3. It can occur naturally in cells or be induced artificially for therapeutic purposes.
4. Unlike gene editing, gene silencing does not necessarily alter the underlying DNA sequence.

Working of Gene Silencing

Gene silencing primarily operates through the following mechanisms:

1. RNA Interference (RNAi)

• A disease-causing gene produces messenger RNA (mRNA), which carries instructions for making proteins.
• Small interfering RNA (siRNA) molecules are designed to target the specific mRNA.
• The siRNA guides cellular machinery to recognise and destroy the target mRNA.
• As a result, the production of the harmful protein is reduced or stopped.

1. Epigenetic Silencing

• Chemical modifications are made to DNA or associated proteins without changing the underlying DNA sequence.
• One such modification is DNA methylation, in which methyl groups are added to DNA, commonly at cytosine bases.
• This can suppress the activity of specific genes by preventing their transcription.
• Consequently, the production of proteins encoded by those genes is reduced.

Application in Hepatitis B Treatment

• Hepatitis B virus (HBV) infects liver cells and uses its genetic material to produce viral proteins and replicate.
• A major challenge in treating chronic Hepatitis B is the persistence of viral genetic material inside infected liver cells.

CRMA-1001: An experimental epigenetic silencing therapy

1. Developed by nChroma Bio, CRMA-1001 aims to suppress the expression of Hepatitis B viral genes through targeted epigenetic modifications.
2. It targets two important forms of viral genetic material:

• cccDNA (Covalently Closed Circular DNA): A stable form of viral DNA that persists inside liver cells and acts as a reservoir for viral replication.
• Integrated HBV DNA: Viral DNA that becomes incorporated into the genetic material of the host cell.
• By suppressing viral gene expression, the therapy aims to reduce the production of viral proteins and potentially contribute to a functional cure.

Inclisiran

1. Inclisiran is an approved RNA interference-based therapy used to reduce low-density lipoprotein (LDL) cholesterol.
2. It targets the messenger RNA responsible for producing PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in liver cells.
3. This reduces PCSK9 protein production, allowing more LDL receptors to remain available on liver cells.
4. Consequently, the liver removes more LDL cholesterol from the bloodstream.

Gene Silencing vs Gene Editing

Applications of Gene Silencing

1. Treatment of viral infections: Helps suppress the expression of viral genes, as being explored for Hepatitis B.
2. Management of cardiovascular diseases: Inclisiran reduces LDL cholesterol through RNA interference.
3. Cancer treatment: Can potentially suppress genes responsible for uncontrolled cell growth.
4. Genetic disorders: May reduce the production of harmful proteins associated with certain inherited diseases.
5. Agriculture: Can help develop crops resistant to viruses, pests and diseases.

Challenges

1. Delivering therapeutic molecules safely to specific cells and tissues.
2. Ensuring long-term effectiveness of gene silencing.
3. Avoiding unintended effects on other genes.
4. Addressing high treatment costs and accessibility.
5. Establishing long-term safety through clinical trials.

FAQs

Q1. What is gene silencing?
Ans: It is the process of reducing or switching off the expression of a particular gene.

Q2. What is RNA interference?
Ans: It is a biological mechanism in which small RNA molecules target messenger RNA and prevent it from producing proteins.

Q3. What is DNA methylation?
Ans: It is an epigenetic modification in which methyl groups are added to DNA, potentially suppressing gene expression.

Q4. What is CRMA-1001?
Ans:It is an experimental epigenetic silencing therapy developed by nChroma Bio to suppress Hepatitis B viral gene expression.

Q5. What is inclisiran?
Ans: It is an RNA interference-based medicine that reduces LDL cholesterol by suppressing the production of PCSK9 protein in the liver.

Q6. How is gene silencing different from gene editing?
Ans: Gene silencing reduces gene expression, whereas gene editing directly modifies the DNA sequence.