siRNA-based Therapeutics in Clinical Trials
The development of novel therapeutics is a constant battle for safe, effective, successful clinical trials that maintain and promote clinical efficacy. RNA interference (RNAi) technology quietly crept into biological disciplines in the 1990s and now provides an alternative treatment option when existing drug technology fails, such as small molecular drugs and monoclonal antibodies. Therapeutically, RNAi functions via delivery of small RNA fragments, including small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA) mimics, and Dicer substrate interfering RNA (dsiRNA). Following the discovery of RNAi in mammalian in 2001, it was promptly realized that this highly specific mechanism of sequence-specific gene silencing tool is likely to be exploited to develop a new group of drugs that interfere with disease-associated genes. Especially, siRNA strategies are applied to address the urgent needs of clinical illnesses, such as rare and common genetic diseases as well as life-threatening diseases (e.g. cancers and degenerative disorders). The tool may be the next-generation technology to revolutionize the drug market.
Development & Delivery System of siRNA Therapeutics
Through a mechanism of RNAi, siRNA molecules can target complementary mRNA strands for specific degradation, causing the inhibition of gene expression. The ability of siRNAs to control gene expression offers a perspective that can be used for novel therapeutics. Actually, over the past decade, at least 21 siRNA therapeutic agents have been developed for over a dozen diseases, such as varying viruses, cancers, and genetic disorders. Like other biological drugs, RNAi-based therapeutics usually need a delivery vehicle to deliver them into the target cells. Therefore, the clinical advancement of various siRNA drugs has been dependent on the development of siRNA carrier systems, including lipid (liposome), bacteria, attenuated virus, and newly biodegradable nanoparticle. Most therapies allow systemic delivery of the siRNA drugs, while others employ ex vivo delivery via autologous cell therapy. The clinical advance in molecular and cellular biology has permitted the improved design of siRNA molecules.
Figure 1. Schemes of representative siRNA delivery platforms that have been used in clinical studies. (A) Liposome, (B) DPC™ and (C) GalNAc-siRNA conjugates. (Hu, 2019)
siRNA-based Therapeutics in Different Diseases
Since the revolutionary demonstration of RNAi, excellent progress has been achieved in understanding and implementing the gene silencing mechanism, particularly in siRNA-based therapeutics. As a therapeutic strategy, RNAi holds an advantage over small molecular drugs, as virtually all genes are susceptible to targeting by siRNA molecules. Despite its tremendous benefits and potential advantages, major challenges in siRNA-based technology remain efficient, unchanged-safe, and target-oriented delivery of siRNA. Through the decades, the history of siRNA discovery and its application have been reviewed in several clinical practices and disease treatments.
Figure 2. Timeline of RNAi discovery and the progress of siRNA in clinical application. (Saw, 2019)
- Orphan/Rare Diseases
- Metabolic Diseases
- Oncology
- Infectious Diseases
A rare disease also referred to as an orphan disease, is an illness that affects a relatively small percentage of the population. Most rare diseases are genetic and characterized by a wide range of symptoms or signals that differ not only in disease to disease but also from patient to patient suffering from the same disease. In August 2018, the Food and Drug Administration (FDA) approved ALN-18328 (patisiran; Onpattro) infusion for the treatment of Phase I/II polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. This drug is a unique siRNAs formulated as a lipid nanoparticle. Lipid nanoparticle technology is served as a delivery system for RNAi therapeutics and gene therapies to protect therapeutic nucleotides from degradation and to promote targeted siRNA delivery into hepatocytes. The approval broke new ground on two distinct aspects: it's the first approved treatment for peripheral nerve disease induced by hATTR and the first drug of siRNA material to receive FDA approval.
Lipid-based carriers of siRNA therapeutics could target the liver in metabolic disorders and are being evaluated in clinical trials for the treatment of hypercholesterolemia. For this indication, a class of chemically modified oligonucleotides that target endogenous RNA regulators of gene expression (microRNAs) are as well under investigation in clinical trials. Emerging self-delivery siRNAs that are covalently coupled with lipophilic moieties display promise for the further development of therapies. Besides the liver, inflammation of the adipose tissues in patients (who suffered obesity and type 2 diabetes mellitus) might be a valuable target for siRNA therapeutics. Administration of siRNAs packaged within glucan microspheres could silence genes in inflammatory phagocytic cells, as could several lipid-based carriers of siRNA.
Treatment options are limited for many cancers; thus, RNAi may be a new opportunity for those with limited options for cancer survival. Currently, certain clinical trials for cancers are underway, including TKM-PLK1, ALN-VSP, APN401, FANG, MRX34, and siG12D LODER, with a diversity of cancers targeted. Among them, TKM-PLK1 (also known as TKM-080301) is an RNAi therapeutics for cancer and is being applied to treat the gastrointestinal neuroendocrine tumor (GI-NET), hepatocellular carcinoma (HCC), and adrenocortical carcinoma (ACC) in clinical trials. APN401 is one of cancer vaccine methods using siRNA to enhance the antitumor immune reactivity that happens in pancreatic cancer.
Infectious diseases offer potential RNAi targets since new individuals are constantly being subjected to chronic infections, such as hepatitis C virus (HCV) and hepatitis B virus (HBV), or exposed to widespread epidemics, such as Ebola virus. These viruses provide attractive targets for RNAi with which RNAi redesign has the ability to compensate for the genomic instability of infectious factors. HBV is typically sexually transmitted and can be a chronic or an acute infection. Though there is a vaccine available, a myriad of the population is infected every year. Notably, TKM-HBV has been developed to eliminate HBV surface antigen found in chronically infected individuals. It is a siRNA therapy targeting three regions of the HBV genome encapsulated in the lipid nanoparticles (LNPs). Moreover, an approach is being tested to treat Ebola with siRNA using TKM-Ebola. This siRNA has gained success in macaques in studies.
siRNA is a potent, specific, and highly successful tool for loss-of-function studies in nearly all eukaryotic organisms. As a reliable provider currently working on the market of RNAi therapeutics, Creative Biolabs pays attention to the design and synthesis of new siRNA drugs or siRNA pathway agents and would like to introduce a series of cost-effective RNAi therapeutic solutions for the research and development of various diseases. If you want to know more about gene therapy or related siRNA custom services, please directly contact us or send an e-mail with your specific request.
References
- Hu, B.; et al. (2019). Clinical advances of siRNA therapeutics. J Gene Med. 21: e3097.
- Saw, P.E.; et al. (2019). siRNA therapeutics: a clinical reality. Sci China Life Sci.
