Scientists are excited over a gene-silencing drug that recently won an approval from the US Food and Drug Administration (FDA). This approval is historic because it is the first of its kind. The drug works by silencing genes that otherwise lead to the production of damaged proteins associated with certain diseases. The drug is called patisiran and it recently got its approval for use to treat the hereditary transthyretin amyloidosis, a fatal rare hereditary condition associated with damaged nerves.
Gene basis of hereditary transthyretin amyloidosis
The hereditary transthyretin amyloidosis is a rare and fatal hereditary condition that manifests as an autosomal dominant neurodegenerative disease. Because it is dominant, this means that the offspring inheriting the defective autosomal gene will acquire the condition. A defective transthyretin (TTR) gene located on human chromosome 18q12.11 is the genetic cause. The most common type of mutation is the replacement of valine by methionine at position 30.
A normal, functional TTR gene codes for transthyretin (TTR) protein that is involved in the transportation of thyroxine (thyroid hormone) and retinol (vitamin A). TTR protein is produced mainly in the liver, and is then secreted into the bloodstream. TTR proteins from a defective TTR gene tend to misfold and stick together, forming amyloids. This building-up of amyloids in tissues is called amyloidosis. In hereditary transthyretin amyloidosis, pathogenic amyloids form especially in the peripheral nervous system, which may eventually lead to a progressive sensory and motor polyneuropathy.
Gene silencing by RNA interference
Normally, the cell performs what is now known as RNA interference (RNAi). It is also known as quelling, co-suppression, and post-transcriptional gene silencing. In this process, the RNA molecules inhibit the translation of a gene. They do so when they neutralize targeted mRNA molecules. RNAi is different from CRISPR, which is a gene-editing tool that makes use of a guide RNA. CRISPR is used to switch off a gene and has a potential therapeutic use to treat cancers. It also had FDA approval in 2016 for use in a clinical trial study. However, recent studies on CRISPR raised issues about its safety since it was found to cause unexpected mutations that involve large deletions and complex genomic rearrangement at target sites.2 To learn more about CRISPR, read: CRISPR caused gene damage? … Unlike CRISPR, the RNAi is presumed not to bring permanent changes to DNA.3
Patisiran as gene-silencing drug
Patisiran is RNA-based drug that recently received the first FDA approval for use as a gene-silencing tool. People with hereditary transthyretin-mediated amyloidosis can now be treated with it. The drug interferes with the production of transthyretin. It doses so by preventing the mRNA involved in the translation of the gene that codes for the problematic protein. This is good news to people with such fatal rare condition. FDA has now approved a drug that can be administered to them. The downside, though, is the chillingly high cost. The cost of the therapy is estimated to be about $450,000 in a year.4
New therapeutic technologies that delve into the molecular and gene mechanisms hold so much promise especially in conditions that until now lack an efficacious treatment. RNAi is a precise gene-silencing tool and scientists are excited in its historic FDA approval. This means that it is a glorious start for contemporary therapies involving targeted gene silencing and alterations. The cost of the therapy may be encumbering but it is still a step forward, certainly a scientific feat to reckon.
— written by Maria Victoria Gonzaga
1 TRANSTHYRETIN; TTR. (n.d.). OMIM.org. Retrieved from https://omim.org/entry/176300
2 Gonzaga, M. V. (17 July 2018). CRISPR caused gene damage? Rise and pitfall of the gene-editor. Biology-Online.org. Retrieved from https://www.biology-online.org/crispr-caused-gene-damage-rise-pitfall-gene-editor/
3 Nield, D. (14 Aug. 2018). A First of Its Kind Gene-Silencing Drug Just Got Historic Approval From The FDA. ScienceAlert. Retrieved from https://www.sciencealert.com/first-drug-silencing-genes-approved-by-fda-for-disease-treatment
4 Lipschultz, B. & Cortez, M. (10 Aug. 2018). Rare-Disease Treatment From Alnylam to Cost $450,000 a Year. Bloomberg. Retrieved from https://www.bloomberg.com/news/articles/2018-08-10/alnylam-wins-first-u-s-drug-approval-in-rare-genetic-disease