What is ONPATTRO (Patisiran)?
ONPATTRO, also known by its generic name patisiran, is a prescription medication used to treat polyneuropathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. hATTR amyloidosis is a rare, progressive genetic disease where a mutation in the transthyretin (TTR) gene causes the liver to produce abnormal, misfolded TTR proteins. These proteins accumulate as amyloid deposits in various organs and nerves, leading to widespread nerve damage (polyneuropathy) and other severe symptoms.
ONPATTRO is designed to address the root cause of this disease by targeting the production of both the abnormal and normal TTR protein. It is composed of a double-stranded small interfering RNA (siRNA) molecule, which is encapsulated within a protective lipid nanoparticle for targeted delivery to the liver, where TTR is primarily synthesized.
The Mechanism of RNA Interference (RNAi)
The mechanism through which ONPATTRO operates is known as RNA interference (RNAi). RNAi is a natural cellular process that regulates gene expression. In the case of ONPATTRO, this process is hijacked to prevent the production of the harmful TTR protein. Here is a breakdown of how the mechanism works:
- Delivery: The patisiran siRNA is delivered via lipid nanoparticles that are specifically designed to target and enter liver cells (hepatocytes).
- Binding: Once inside the cell, the siRNA molecule is incorporated into a cellular machinery known as the RNA-induced silencing complex (RISC). The RISC uses the siRNA to find and bind to the specific messenger RNA (mRNA) that carries the genetic instructions for making the TTR protein.
- Degradation: Following the binding, the RISC complex cleaves and degrades the TTR mRNA.
- Silencing: By destroying the mRNA blueprint, the cell's protein-making machinery is unable to produce the TTR protein, effectively "silencing" the gene.
This reduction in TTR protein production lowers the circulating levels of TTR in the blood, which, over time, can help reduce the accumulation of amyloid deposits in tissues.
Differentiating RNAi from Traditional Gene Therapy
The fundamental difference between ONPATTRO's RNAi mechanism and traditional gene therapy lies in their targets and the permanence of their effects. While both methods address genetic diseases, they do so at different levels of the genetic process.
- Target: Traditional gene therapy aims to introduce a healthy, functional copy of a gene into a patient's cells to replace or correct a faulty one by modifying the DNA itself. In contrast, ONPATTRO's RNAi mechanism does not alter the patient's DNA. It targets the transient messenger RNA (mRNA) molecule, which is the intermediate step between the DNA blueprint and protein production.
- Permanence: Traditional gene therapy, if successful, can lead to a long-lasting, and potentially permanent, therapeutic effect by correcting the underlying genetic defect. Because ONPATTRO targets the temporary mRNA, its effect is not permanent. The treatment must be administered as a recurring intravenous infusion every three weeks to maintain the gene-silencing effect.
The Terminology: "Gene Silencing" vs. "Gene Therapy"
The use of the term "gene silencing" for RNAi therapies like ONPATTRO can lead to confusion, as it sounds similar to gene therapy. The distinction, however, is crucial. Gene silencing simply means preventing a gene from being expressed or translated into a protein. RNAi is one method of gene silencing. While some organizations, like the American Society of Gene & Cell Therapy, may use "gene therapy" in a broader sense to refer to any therapy that targets genes, the technical and pharmacological distinction is important for understanding the mechanism and implications of the treatment.
Comparison Table: ONPATTRO (RNAi) vs. Classical Gene Therapy
| Feature | ONPATTRO (Patisiran, RNAi) | Classical Gene Therapy |
|---|---|---|
| Mechanism | Uses siRNA to degrade messenger RNA (mRNA). | Modifies or introduces new DNA into the cell. |
| Target | The mRNA blueprint for a protein. | The underlying DNA sequence. |
| Permanence | Temporary effect; requires repeat dosing. | Aims for a long-lasting or permanent correction. |
| Delivery | Lipid nanoparticles delivered intravenously. | Viral or non-viral vectors delivered to target cells. |
| Dosage Frequency | Every three weeks. | Typically a one-time treatment, though repeat dosing may be needed. |
The Implications for Treating Genetic Diseases
ONPATTRO's approval as the first siRNA therapeutic marked a significant milestone for RNA-based medicine. This approach offers a powerful alternative to traditional genetic therapies, particularly for diseases driven by the overexpression of a particular protein. For patients with hATTR amyloidosis, ONPATTRO offers a much-needed solution that addresses the root cause of the disease, providing a more effective way to manage symptoms and slow progression compared to older, less targeted treatments. The success of ONPATTRO has paved the way for further research and development into other RNAi therapies for a wide range of genetic and rare disorders.
Conclusion
In conclusion, while ONPATTRO effectively silences a gene to treat a genetic disease, it is not a traditional gene therapy. It utilizes RNA interference to degrade the messenger RNA transcript, preventing protein synthesis without permanently altering the patient's DNA. This makes ONPATTRO a groundbreaking RNAi therapeutic, showcasing a powerful new class of medicine for genetically-driven conditions. The nuanced distinction in its mechanism is key to understanding this innovative treatment and its place in the landscape of modern medicine.
