Hereditary transthyretin amyloidosis (hATTR) is a severe, adult-onset inherited systemic disease which can affect the peripheral and autonomic nervous system, heart, kidney and the eyes. (1)
TTR (transthyretin) is a protein found in blood plasma and blood serum as well as in the cerebrospinal fluid (CSF). The protein is mainly synthesized (assembled) by the liver and the choroid plexus (CP). The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. The protein is created by a process called biosynthesis. Biosynthesis is carried out in accordance with genetic instructions encoded from ones DNA. The DNA instructions create messenger RNA (mRNA), which in turn biosynthesize transthyretin proteins in the form of a tetramer. (2)
In the case of hereditary amyloidosis, a DNA mutation causes an errant mRNA signal, which results in destabilization of the tetramer and misfolding of the protein. The misfolded TTR proteins aggregate into amyloid fibrils as shown in the figure below. (3) The Amyloid then deposits throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastro-intestinal, etc. in nature.
RNA interference (RNAi) is a natural process that controls gene “expression” to messenger RNAs (mRNA), thus blocking the RNA instruction for creating a protein.
The figure shown below illustrates this process. (4) In basic terms, the interfering process begins with a long double-stranded RNA (dsRNA) being “diced” into small fragments by an enzyme called a “Dicer”. These fragments, referred to as small interfering RNAs (siRNA), bind to proteins called argonaute proteins. After binding to an argonaute protein, one strand of the double-stranded RNA is removed. The remaining strand then binds to the targeted messenger RNA. The argonaute protein then cleaves the messenger RNA, destroying it.
RNA interfering therapeutic medicines mimic this natural process, utilizing designed small interfering RNAs (siRNA) that ultimately bind to and destroy disease-causing RNA. As a result, the cell is no longer able to produce the misfolded Amyloid protein. One such therapeutic is the drug Vutisiran, used to treat hereditary amyloidosis with polyneuropathy. The figure shown below shows how Vutisiran carries out the same silencing process. (5)
For additional information on ATTR Treatments such as stabilizers and silencers, please view the short Expert Insights video below by Dr. Brett W. Sperry from our Amyloidosis Lecture Series.
Sources —————————————–
- Carroll, A., Dyck, P. J., Carvalho, M. de, Kennerson, M., Reilly, M. M., Kiernan, M. C., & Vucic, S. (2022, June 1). Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. Journal of Neurology, Neurosurgery & Psychiatry. https://jnnp.bmj.com/content/93/6/668
- “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
- Diagnostic Algorithm for Transthyretin Amyloidosis with Lower… | Download Scientific Diagram, researchgate.net/figure/Diagnostic-algorithm-for-transthyretin-amyloidosis-with-lower-gastrointestinal_fig1_348081318. Accessed 28 Oct. 2024.
- “What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.
- “RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai
