Prospects of RNAi in Cancer Therapy
RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer.
RNAi Overview
RNA interference (RNAi), a process that involves sequence-specific gene silencing, is an endogenous post-transcriptional regulation process that consists of non-coding RNAs like microRNAs (miRNAs), small interfering RNAs (siRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which target and silence messenger RNAs (mRNAs) in a sequence-specific manner. With the added benefit of simultaneously targeting multiple genes that share homology, RNAi is fast, economical, and has the potential for site-specific targeting. The primary role of RNAi in cells would be to downregulate the expression of their target gene and thereby the encoded proteins thus bringing about the desired results. Through careful sequence selection and synthesis of tailored non-coding RNAs (ncRNAs), this powerful approach could be used to circumvent conventional cancer therapy limitations, thus paving the way for next generation therapeutics.
Fig. 1 Schematic illustration of RNAi mechanism.
General Application of RNAi
Given its target site specificity and therapeutic potential, RNAi is currently used in many research fields. The following parts will briefly describe some applications of RNAi in biomedicine.
| Typical Disease Fields |
| Neurodegenerative Disease | Cardiovascular Disease | Viral Infection |
| Lung Cancer | Pancreatic Cancer | Breast Cancer |
| Colorectal Cancer | Other Cancers | |
The only RNAi drug on the market is called rintatolimod, with the United States trade name Ampligen. Rintatolimod is a double-stranded RNA drug first launched in Argentina in 2017 for the treatment of severe myalgic encephalomyelitis/chronic fatigue syndrome. Currently, some progress has been made in preclinical studies. Phase I and I/II clinical trials are ongoing at AIM ImmunoTech (formerly HemispheRx) to evaluate its vaccine adjuvant potential for the treatment of stage II–IV HER2+ breast cancer, triple-negative breast cancer, and several other solid tumors, such as renal cell carcinoma, pancreatic cancer, and ovarian cancer. The molecular mechanism is Toll-Like Receptor 3 agonists, and it was found that the activation of TLR3 in vitro can induce apoptosis in lung cancer cell lines. In addition, some studies support the use of TLR3 agonists in patients with non-small cell lung cancer (NSCLC) to reactivate the local innate immune response.
Genasense (oblimersen) is an antisense oligonucleotide drug specific to Bcl-2. Genasense can specifically bind to human Bcl-2 mRNA, which leads to the catalytic degradation of Bcl-2 mRNA and reduces the translation of Bcl-2 protein. Therefore, researchers can use mRNA degradation strategies and small inhibitory molecules for targeted Bcl-2 therapy in a variety of cancers, such as breast cancer, colon cancer, and prostate cancer.
- RNAi drugs in other diseases
Since the first RNAi drug was launched, some RNAi drugs (such as HBV-ISS, mipomersen sodium, nusinesen, inotersen, volanesorsen, patisiran/onpattro, pegaptanib sodium, and viltolarsen) have been used in clinical treatment and have shown unparalleled advantages over other types of drugs.
Delivery Systems for RNAi Drugs
Great efforts have been made to design and develop various carriers to overcome the obstacles in the delivery process. In general, these carriers can be divided into two categories: viral vectors and non-viral vectors.
- Lipid-based delivery system
Various lipid-based siRNA delivery systems have been reported, including liposomes, solid LNP, micelles, and emulsions. In fact, LNP is considered a popular vector because of its good stability and high transfection efficiency.
Fig. 2 (A) Liposome. (B). Formation and secretion of exosomes.
- Polymer-based delivery system
Many types of cationic polymers have been studied as carriers; one of the types is synthetic polymer (polycation containing cyclodextrin (CD), PEI, etc.) and the other is natural polymer (chitosan).
Perspectives
To date, cancer remains the leading cause of death in humans, further uncontrolled proliferation and aggressiveness of cancer cells render many medical treatments ineffective. The remarkable gene silencing capabilities of siRNA therapy offer a glimpse into the future, offering new strategies for the treatment of cancer and other diseases.
References:
- Tian, Z.; et al. Insight into the prospects for RNAi therapy of cancer. Frontiers in Pharmacology. 2021, 12: 644718.
- Mahmoodi.; et al. Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach. International journal of nanomedicine. 2019: 3111-3128.
- Swaminathan, G.; et al. RNA interference and nanotechnology: A promising alliance for next generation cancer therapeutics. Frontiers in Nanotechnology. 2021, 3: 694838.
* For research use only. Not intended for any clinical use.