RNAi: Bench to Clinic

Minghao Li- Ph.D. Candidate

RNAi: Bench to Clinic- Written by Minghao Li, Ph.D. Candidate

How RNAi Works

Although our DNA encodes our genetic identity and serves as the instructions for cellular functions that allow us to live, messenger RNA(mRNA) transcribed from our DNA is actually used to carry out these orders. RNA interference (RNAi) is a natural process in our cells that prevents the successful completion of certain RNA orders. Since its initial discovery in 1998 [1], scientists have further unraveled the mechanisms of how RNAi prevents certain mRNAs from being translated. The active molecules that were determined to activate RNAi interference are short double-stranded RNA (dsRNA) oligonucleotides approximately 21 nucleotides in length and are now termed siRNA (small interfering RNA) [2]. A special enzyme native to cells called DICER is responsible for cutting longer dsRNA into the approximately 21 nucleotides that form these siRNAs [3]. The siRNA, which is complementary to and thus specific for the target gene of interest, is then loaded onto the RNA-induced silencing complex (RISC) which then precedes to cleave the targeted mRNA [4]. This process is depicted in the figure below [5].

Therapeutic Market: 1st FDA Drug Approved

In August of 2018, the FDA approved the first RNAi drug ONPATTRO, which is marketed by Alnylam Pharmaceuticals for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (hATTR), an orphan disease affecting less than 200,000 people in the US [6, 7]. hATTR is caused by a mutation in the gene for transthyretin, a protein that is mainly generated in the liver and is important for transporting vitamin A [8]. These mutations in transthyretin cause the protein to fold improperly, leading to the accumulation of protein deposits called amyloid fibrils. These amyloid fibrils accumulate throughout the body and cause the symptoms of hATTR such as loss of sensation, limb weakness and pain, digestive issues, and heart-related issues [9]. Delivery systems are one of the obstacles faced by siRNA based therapeutics. ONPATTRO packages the siRNA into a lipid nanoparticle that travels to the liver after intravenous infusion, directly preventing or altering mutant transthyretin production. The image below briefly describes the treatment process [10].

The current global antisense and RNAi therapeutics market is forecasted to grow at a CAGR of close to 9% from 2019 to 2023 [11]. The major factor contributing to the global growth of market is the high target affinity and specificity of RNAi therapeutics, with Alnylam's FDA approval driving much of the recent growth. A key challenge for this market's future growth is the high price of RNAi drugs due to the difficulty in developing an accurate delivery system [12]. The higher pricing may reduce patient access to these drugs and thus impede long-term growth.

Potential Drug Delivery Methods

A major barrier to entry for future RNAi drugs is the difficulty of proper drug delivery. As transthyretin is mainly produced in the liver, Alnylam Pharmaceuticals was able to simply encapsulate the siRNA into a lipid nanoparticle for liver-specific delivery after intravenous infusion. However, effective methods for targeting other cell types or other organ locations have not yet been developed. This is especially complicated by the fact that RNAs are charged molecules that cannot easily penetrate the cell's membrane. Additional delivery methods under development include fusing the siRNA to antibodies or cholesterol and using viral delivery systems to express the siRNA [13]. The difficulty in accurately delivering the fragile siRNAs to the treatment cells caused many pharmaceutical companies to leave this market; nevertheless, Alynylam's recent success is spurring renewed interest [14].


1. https://www.nature.com/articles/35888

2. https://www.thermofisher.com/us/en/home/life-science/rnai/rna-interference-overview.html

3. https://www.sciencedirect.com/science/article/pii/S0092867404002934?via%3Dihub#aep-section-id7

4. https://www.nature.com/articles/418244a

5. https://commons.wikimedia.org/wiki/File:ShRNA_Lentivirus.svg

6. https://www.onpattro.com/hcp/?gclid=CjwKCAjw4LfkBRBDEiwAc2DSlM9GdqIjWrzsnvR-RymYMipLXY5Sz2y8ozUbN1Li5LI7O5HNDJ5obRoCO9gQAvD_BwE&gclsrc=aw.ds

7. https://amyloidosis.org/fda-approves-two-treatments-for-hattr-amyloidosis-in-2018/

8. https://hattrbridge.com/about-hattr-amyloidosis/cause-and-symptoms

9. https://www.alnylam.com/patients/amyloidosis/

10. https://www.onpattro.com/treatment-onpattro

11. https://www.businesswire.com/news/home/20181130005142/en/Global-Antisense-RNAi-Therapeutics-Market-2019-2023-High

12. https://www.prnewswire.com/news-releases/the-global-market-for-antisense--rnai-therapeutics-is-projected-to-grow-at-a-cagr-of-8-67-during-2019-2023--led-by-alnylam-pharmaceuticals-bausch-health-biogen-and-sarepta-therapeutics-300752886.html

13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978219/

14. https://www.pharmaceutical-journal.com/news-and-analysis/features/rna-interference-therapies-could-be-on-the-cusp-of-success/20204853.article?firstPass=false