#10 RNA-Based Therapies


If you reflect back on your middle school science class, you might remember the concept of the central dogma. Used by geneticists for decades, the central dogma states that in the cells of the body, DNA is transcribed to RNA that is then translated into proteins. Proteins, the large molecules created from sequences of RNA, are responsible for many tasks in the body. Often associated with the body’s structure, functioning, or regulation, functional proteins are the key to healthy cells.

When proteins are damaged and non-functioning, health is compromised. It is these non-functioning or misfolded proteins that are the culprit in many genetic disorders. In new efforts to avoid misfolded proteins and remedy the genetic disorders plaguing members of our society, scientists are reflecting back to the dogma.
As the central intermediary in the expression of genetic information, RNA has become a popular target for therapeutics. Interfering with genetic data at the RNA level gives scientists the ability to intercept a patient’s genetic abnormality before it is translated into functioning (or nonfunctioning) proteins. Today, the most popular and successful mechanisms of RNA therapy include antisense nucleotides and RNA interference.

Antisense nucleotides are particles of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) that are complementary to a messenger RNA (mRNA) molecule – the RNA molecule that encodes a protein. Because these molecules are complementary to the given strand of mRNA, they bind to form a free double stranded molecule or double-stranded region of a chromosome. The then double-stranded region of the mRNA is unable to interact with ribosomes and, as a result, is unable to be translated into the protein of choice. Inhibiting the production of the protein encoded by the disease mutation mitigates the presence of the toxic proteins and the disorder.

Antisense nucleotide therapy is being explored in several conditions. To date, there are a few FDA approved antisense nucleotide therapies for the treatment of conditions such as AIDS-related retinitis and familial hypercholesterolemia. But innovative work in the space is focused on the treatment of the rare neurological disorder, Huntington’s disease. The goal of this strategy is to reduce the amount of abnormally large huntingtin (HTT) protein being produced in the cells of Huntington’s patients. Several nucleotide molecules are under clinical investigation in the form of phase I and II testing.

RNA interference is a natural regulatory mechanism in which RNA molecules inhibit gene expression by neutralizing targeted mRNA sequences. Andrew Fire and Craig Mello won the 2006 Nobel Prize in Physiology and Medicine for the discovery of this pathway. In RNA interference, one of two types of RNA molecules – either microRNA (miRNA) or short interfering RNA (siRNA) – is used to silence genes. MicroRNAs are short RNA molecules that bind to a part of the mRNA and trigger either the degradation process or sterically hinder protein production. Short interfering RNAs are a class of double-stranded RNA molecules functionally similar to microRNAs. Artificially, either of these molecules can be designed to target and suppress condition-specific defective genetic sequences. Known by other names such as co-suppression, post-transcriptional gene slicing, and quelling, RNA interference has shown immense potential.

RNA interference therapy is currently being explored for use in cancer and neurological diseases. Alzheimer’s disease is poised to be the most important application for RNA interference therapy if significant headway is made. The most successful RNA interference therapy to date, is for the treatment of hereditary transthyretin-mediated amyloidosis. Hereditary transthyretin-mediated amyloidosis is a genetic disease that causes buildup of abnormal amyloid protein in the peripheral nerves of the heart and body. In early 2018, the FDA accepted an NDA for this new therapy and granted priority review with a pending action date of August 2018. On August 10, 2018, the therapy received its anticipated approval and became the first FDA approved small interfering RNA interference therapy. The therapy also represents the first and only treatment for the incredibly rare, life-threatening disease.

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