RNAi Therapy: Out of the dark, a whole new era has come

Lumasiran and two other FDA-approved RNAi therapies, patisiran and givosiran, have been developed by U.S. biopharmaceutical company Alnylam Pharmaceuticals, all of which are used to treat rare genetic diseases.
Patisiran was approved in 2018 to treat family amyloid polyneuropathy (TTR-FAP) of thyroxine protein, and Givosiran was approved in 2019 for the treatment of acute hepatosis.
December, the European Union approved the launch of Novarid-developed RNAi lipid-lowering therapy inclisiran for the treatment of hypercholesterolemia and mixed lipid abnormalities in adults.
this is a breakthrough drug in the blood lipid field, and its EU approval is a milestone, marking the first success of RNAi therapy in a common disease.
Inclisiran is also targeted at PCSK9 targets, Phase III clinical data is very good, in addition to good tolerance, high safety characteristics, but also has the advantages of good drug compliance.
Inclisiran was given by subderpose injection, with a three-month interval between the first two doses and then every six months, equivalent to a patient receiving only two subsurfic injections a year to maintain a stable and effective reduction in LDL-C.
Incisiran was also developed by Alnylam Pharmaceuticals, but The Pharmaceuticals Company was granted a global exclusive license and Novartic acquired The Pharmaceuticals Company for $9.7 billion at the end of 2019.
20 years from the first discovery of RNAi to the launch of the first RNAi therapy, the RNAi field has experienced numerous obstacles and setbacks along the way, but is now moving into a new era.
In 1998, biologists Andrew Fire and Craig Mello published a study in Nature that for the first time imported double-stranded RNA into beautiful cryptosomal worm cells and found that double-stranded RNA was more efficient than single-stranded RNA in blocking the expression of genes, a phenomenon they call RNA interference.
also won the 2006 Nobel Prize in Physiology or Medicine for this groundbreaking discovery.
source: Nobel's website In the early 2000s, the discovery also attracted great interest from researchers who wanted to use RNAi as a technology in basic science and therapeutic fields.
RNAi could target the protein's production process as long as the genetic coding sequence of any pathogenic protein is known.
, research has sprung up on a variety of diseases, including rare genetic diseases, cancers and infectious diseases.
, however, the results of early clinical trials have been less than satisfactory, and low efficacy and harmful side effects have prevented the treatment from making significant progress.
Bevasiranib was one of the first RNAi therapies to enter Clinical Phase III trials, developed by OPKO Health to treat macular degeneration, but the clinical trial was terminated in 2009 due to poor early results.
2010, pharmaceutical giants such as Roche, Pfizer and Mercedon shut down their RNAi research projects, and RNAi therapy development entered the "dark ages."
The approval of the third RNAi therapy, lumasiran, is a huge milestone for the RNAi field," said Derek Dykxhoorn, a molecular geneticist at the University of Miami.
" Dykxhoorn said, because siRNA is easily degraded by enzymes in the blood, the main obstacle to the development of therapy is the accurate delivery of sufficient amounts of small interfering RNA (siRNA) to specific cells in the body.
to solve this problem, scientists continue to work the development of siRNA packaging methods.
an early, effective technique for packaging siRNA in lipid nanoparticles (LNP).
but these LNP also have some drawbacks.
For example, although LNP carrying siRNA accumulates in the liver as blood flows, the liver is not a clear target organ for therapy, and the researchers want a highly selective approach to tissue delivery.
GalNAc is another delivery technology developed by Allenlam that connects N-acetyl semi-lactamine to siRNA.
on the surface of the liver cells identifies N-acetyl semi-lactamine, which allows highly specific access to liver cells while limiting off-target effects.
used in many therapies developed by Alnylam, including lumilan.
the delivery of GalNAc-siRNA couples into liver cells (source: Nucleic Acid Therapeutics) to extend the target beyond the liver is the next big test.
trials of RNAi therapy at targets outside the liver are still in their early stages.
to play a role in other organs, researchers need to find a similar approach to GalNAc.
RNAi therapy for liver disease, there are also research therapies in the central nervous system and eye areas in Allylam's pipeline.
: The success of Alnylam's official website, Alnylam, shows that RNAi has become a platform technology.
other biotech companies, such as Dicerna Pharmaceuticals and Arrowhead Pharmaceuticals, are also working on RNAi drug pipelines.
" has a lot of work to do, and that's just the beginning.
," said Dr. Pritesh Gandhi, vice president and general manager of alnylam's lumasiran program.
: 1 s RNA Interference Comes of Age (Source: TheScientist) 2 s Aaron D. Springer, Steven F. Dowdy. GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Therapeutics (2018) 3# Ray, K. K., Wright, R. S., Kallend, D., Koenig, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. New England Journal of Medicine (2020) 4 "Silence" brings a breakthrough - interpretation of the 2006 Nobel Prize in Physiology or Medicine (Source: World of Life)