RNAi Therapeutics Expand Beyond the Liver as siRNA Drug Development Accelerates
核心洞察
RNA interference (RNAi) therapies using small interfering RNA (siRNA) are already approved by the FDA, with at least seven treatments available for genetic diseases and more in clinical trials.
The global RNAi therapeutics market is projected to grow from about $1.5 billion in 2024 to roughly $5.1 billion in 2034, reflecting rapid commercial expansion.
Delivery beyond the liver is a key frontier, with researchers developing siRNAs targeting muscles, nerves, the placenta, and other organs.
Small interfering RNA (siRNA) therapies, once confined largely to the liver, are now expanding their reach to tissues throughout the body as pharmaceutical developers race to translate RNA interference (RNAi) into a new class of medicines. The technology, which suppresses gene expression by triggering the destruction of specific messenger RNA (mRNA), has moved from science fiction to clinical reality, with at least seven siRNA-based drugs approved by the U.S. Food and Drug Administration for treating a variety of genetic diseases and others advancing through clinical trials.
RNA is a nucleic acid involved in the process of making proteins. Messenger RNA transmits genetic information from DNA to help synthesize proteins. When an siRNA therapy induces the breakdown of a specific mRNA, it blocks the very process by which a problem-causing protein is produced, thereby suppressing gene expression. Small interfering RNAs, including naturally occurring microRNAs and their synthetic counterparts, work between the copying and protein-building steps to set levels of protein production. These interfering RNAs are tiny—just 21 or 22 RNA building blocks, or bases, long—whereas mRNAs may stretch for hundreds to thousands of bases.
Interfering RNAs share short runs of bases with specific mRNAs. When the little RNAs match up with the target mRNA, the longer partner is scheduled for destruction. This occurs in a naturally occurring bit of cellular machinery called RISC, where mRNAs that have interfering RNAs attached are chopped up, preventing proteins from being made and essentially silencing the corresponding genes.
siRNAs used as therapies work like natural interfering RNAs but are synthesized to have their own properties. "They're fully chemically modified," said Anastasia Khvorova, a chemical biologist at the University of Massachusetts Chan Medical School's RNA Therapeutics Institute in Worcester. The modifications make them stable in the body and send them to the correct organ. So far, all the FDA-approved siRNAs work in the liver. Khvorova and colleagues are developing others that can be dispatched to muscles, nerves, the placenta, or to other organs.
Usually, siRNAs don't completely shut off a gene, but they can knock it down enough that negligible levels of protein get built, according to Judy Lieberman, an immunologist at Boston Children's Hospital and Harvard Medical School. Lieberman has also been an advisor to Alnylam, the company that first solved the problem of delivering siRNAs to specific cells.
One notable characteristic of siRNA therapies is their durability. "They tend to last," said Gane Ka-Shu Wong, a physicist-turned-biomedical scientist at the University of Alberta in Edmonton, Canada. Current siRNA therapies may last for six months or longer with a single dose. This persistence also means that reversing a gene-silencing effect is not instantaneous. "He could reverse it," Lieberman said, "but it might take a few days," noting that it could take a few hours to make mRNA copies and get new proteins, and probably longer to return to full function.
Global pharmaceutical companies are accelerating the development of siRNA therapies. Novartis commercialized Leqvio, an siRNA-based treatment for high cholesterol, and last year strengthened its portfolio by acquiring RNA therapeutics developer Avidity Biosciences for $12 billion. Arrowhead confirmed the efficacy of its siRNA therapy Redemplo (搜索) in a Phase 3 trial for severe hypertriglyceridemia (搜索), following its use for familial chylomicronemia syndrome (搜索). According to one market research firm, the global RNAi therapeutics market is expected to grow from about $1.5 billion in 2024 to about $5.1 billion in 2034.
RNA-based drug development is also thriving in Korea. OliX (搜索) is developing an siRNA therapy that suppresses the expression of specific genes and is expanding its delivery range beyond the liver to tissues such as the eyes and fat tissue. rznomics (搜索), by contrast, has built an editing technology that uses RNA-replacing enzymes to remove disease-causing RNA and replace it with therapeutic RNA. Last year the two companies signed technology transfer deals with Eli Lilly worth 900 billion won ($626 million) and 1.9 trillion won ($1.32 billion), respectively, marking achievements in the global market.
AprilBio (搜索) last month signed a deal to license a dual-target siRNA-based metabolic disease drug candidate from Curigin (搜索), another Korean company. The candidate targets metabolic disorders such as dyslipidemia (搜索). Its distinguishing feature is that it is designed to suppress the expression of two genes simultaneously with a single siRNA.
The technology's real-world relevance has even entered popular culture, with the recently released film "Spider-Man: Brand New Day" featuring the concept of suppressing gene expression using RNAi technology. In the film, the Hulk advises Spider-Man to keep his abilities in check using siRNA. As Khvorova noted, shutting down foreign DNA—such as inserted arachnid DNA—or mutated genes is "absolutely, that is theoretically what is feasible." However, she cautioned that genes don't work in isolation, and shutting one down may have unintended consequences for others.