March 3, 2024

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Will RNA therapy play the more important role in future?

Will RNA therapy play the more important role in future?


Will RNA therapy play the more important role in future?

The Human Genome Project (HGP) has revealed a wealth of information about the human genome and greatly enhanced its role in the development of biomedical research.

Thanks to advances in next-generation sequencing technology, researchers have been able to uncover the role of some genetic factors in many diseases, such as cancer, rheumatoid arthritis, Parkinson’s disease and Alzheimer’s disease.


In addition, many research results have revealed the important roles of coding and non-coding RNAs ( ncRNAs ), such as miRNAs, long ncRNAs (lncRNAs ) , circRNAs, and siRNAs.

This lays the groundwork for the development of possible treatments for various diseases by introducing nucleic acids into cells to permanently or transiently control the expression of altered genes. In addition, the development of various delivery systems can deliver RNA to the target site, addressing the problems posed by the inherent instability of RNA.

As a result, many RNA-based therapeutics involving siRNA, ASO, ribozymes, mRNA, aptamers, and CRISPR/Cas have been developed and are undergoing clinical trials in various diseases. RNA-based drugs show excellent application potential, and the era of RNA therapy is coming.


Will RNA therapy play the more important role in future?



siRNA is produced by the endonuclease process by the ribonuclease Dicer, an endonuclease belonging to the RNase III family that produces 21-25 nucleotide double-stranded RNA.

Once generated, Dicer transfers the siRNA to the RNA-induced silencing complex ( RISC ), which contains Argonaute 2 that degrades target mRNA molecules. Because of this ability of siRNAs, they have been proposed as a possible therapeutic approach.


siRNA therapies are being tested in multiple cancer treatments. siG12D-LODER is a biodegradable polymer matrix containing siRNA against KRASG12D, and clinical studies ( NCT01188785 ) have shown that the polymer is able to target tumors and inhibit tumor progression. A further study ( NCT01676259 ) is currently underway to test the efficacy of siG12D-LODER in combination with chemotherapy drugs such as gemcitabine and nab-paclitaxel in patients with locally advanced pancreatic cancer.


Polo-like kinases ( PLKs ) are involved in cell cycle regulation and cell proliferation and are often overexpressed in cancer cells, and inhibition of Plk reduces cancer cell proliferation.

TKM-080301 is a lipid nanoparticle ( LNP ) formulation consisting of four lipids and a synthetic double-stranded siRNA against human PLK1 mRNA.

Intravenous infusion of TKM-080301 was well tolerated, but showed only limited antitumor effects and no overall survival effect in patients with advanced hepatocellular carcinoma. However, TKM-080301 showed some tumor suppressor effect in adrenocortical carcinoma ( ACC ).


Protein kinase N3 ( PKN3 ) is a downstream effector of the phosphoinositide-3-kinase ( PI3K ) pathway, and blocking PKN3 can inhibit tumor progression and lymph node metastasis.

Atu027 , a liposomal PKN3 siRNA formulation, showed a favorable safety profile in patients with advanced solid tumors, with stable disease in 41% of subjects at the end of treatment. In subsequent studies, the combination of Atu027 and gemcitabine in locally advanced or metastatic pancreatic cancer showed good safety and tolerability.Image


In addition to the field of cancer, the application of siRNA in other disease areas is also actively developed.

Inclisiran , a phosphorothioate, 2′-O-methyl nucleotide and 2′-fluoronucleotide modified siRNA targeting PCSK9, subcutaneous injection has been shown to reduce PCSK9 levels in patients with high cardiovascular risk and LDL cholesterol levels.

And it is only injected once every six months, showing excellent patient compliance. On December 11, 2020, Inclisiran was approved for marketing in the European Union.


Numerous siRNA studies targeting choroidal neovascularization caused by age-related macular degeneration ( CNV-AMD ), targeting vascular endothelial growth factor receptor-1 ( VEGFR1 ) or RTP801, have shown positive outcomes at various stages of clinical trials desired results, such as AGN211745 and PF-04523655 .

In addition, QPI-1007 , an siRNA that inhibits caspase 2 expression, was well tolerated and improved vision in patients with optic atrophy.


In addition, siRNA therapy has shown promising applications in autosomal recessive primary hyperoxalurias ( PHs ), hepatitis B virus ( HBV ) and liver and idiopathic pulmonary fibrosis.




Antisense nucleic acids ( ASOs ) are single-stranded RNA/DNA molecules of 18-30 base pairs designed to specifically inhibit mRNA function. They bind complementary to specific mRNAs and block mRNA translation or degrade mRNA through RNase H.


Many preclinical and clinical trials of ASO in the treatment of ocular diseases have shown promising results.

Leber congenital amaurosis ( LCA ) causes retinal dystrophy due to intronic mutations in various genes including centrosomal protein 290 ( CEP290 ), causing blindness or severe visual impairment in adolescents.

QR-110 is a single-stranded, phosphorothioated, 2’O-methyl-modified splicing-regulating RNA oligonucleotide for targeting CEP290.

Clinical studies ( NCT03140969 and NCT03913143 ) showed that intravitreal injection of QR-110 reconstituted CEP290 levels in fibroblasts from LCA patients with good tolerability and safety.




Aptamers are single-stranded nucleic acid ( DNA or RNA ) molecules that bind and inhibit proteins.

The ability of aptamers to form shapes provides high affinity and excellent specificity for the target, and aptamers are also known as chemical antibodies due to their mode of action similar to that of antibodies.

Currently, a variety of aptamers have entered clinical trials for various diseases, such as macular degeneration, diabetic macular edema, and chronic inflammatory diseases.


Will RNA therapy play the more important role in future?


EYE001 , a PEGylated aptamer of VEGF, has been shown to completely reduce VEGF-mediated vascular leakage, inhibit retinal neovascularization, and improve vision in an in vitro model.

Studies of EYE001 alone or in combination with photodynamic therapy in patients with CNV-AMD have shown significant visual stabilization or improvement.


In addition to VEGF, the complement pathway also plays an important role in AMD.

Clinical studies of Zimura , a pegylated single-stranded nucleic acid aptamer targeting complement factor C5 and pegcetacoplan targeting C3 and C3b, have shown that subcutaneous injections reduce geographic-like atrophy ( GA ) secondary to AMD, without adverse events.


In addition, ARC1779 , an aptamer targeting the vWF A1 domain, was shown to be well tolerated and the ability to inhibit vWF-dependent platelet function in patients with thrombotic thrombocytopenic purpura in a clinical trial ( NCT00632242 ).

Emapticap-pegol ( NOX-E36 ) is an aptamer targeting CCL2, subcutaneous injection of Emapticap in type 2 diabetic patients with proteinuria showed good tolerance and inhibition of the CCL2/CCL2 receptor axis ability.




Ribozymes are molecules that catalyze RNA, hybridize to target RNA and cause RNA degradation, thereby inhibiting the production of specific proteins.

Importantly, ribozymes can function without cellular proteins.


RPI.4610 ( Angiozyme ) is a chemically stable anti-VEGFR-1 ribozyme that has demonstrated favorable safety, bioavailability and tumor localization in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

However, it failed to demonstrate clinical efficacy in metastatic breast cancer patients.


OZ1 , a tat-vpr-specific anti-HIV ribozyme delivered by autologous CD34+ cells, showed a significant increase in CD4+ lymphocytes in a clinical trial ( NCT00074997 ), suggesting that cell-delivered gene transfer is equally reliable in maintaining ribozyme safety and activity .


Despite the success in many clinical trials, there have also been reports of lack of efficacy and safety, such as Ad5CRT targeting human telomerase reverse transcriptase ( hTERT )-encoding RNA in patients with gastrointestinal cancer , metastatic breast cancer Vascular enzymes or chimeric ribozymes in cancer patients.

Therefore, ribozymes still need to be improved in terms of stability, in vivo activity, co-localization, delivery to specific cells, and sustained stable and long-term expression.




mRNA-based therapies represent a relatively novel and highly potent class of drugs. Several recently published studies have highlighted the potential efficacy of mRNA vaccines in the treatment of different types of malignancies and infectious diseases where traditional vaccine strategies fail to elicit protective immune responses.


Infectious disease vaccines are currently the leading application of mRNA therapy. Moderma and Pfizer’s COVID-19 vaccines have proven safety and efficacy in billions of people, showing strong future application prospects, and I won’t repeat them here.


Will RNA therapy play the more important role in future?


Currently, mRNA vaccines against tumors are available in 2 ways: i) using in vitro loaded or electroporated DCs, and ii) by direct injection of mRNA with or without vector.


In several clinical trials of DC-based mRNA vaccines in cancer patients, vaccination with mRNA encoding a melanoma-associated antigen in combination with TriMix resulted in impressive tumor regression in advanced melanoma.

mRNA vaccines are currently being developed into combination therapies, including chemotherapy, radiotherapy, and checkpoint inhibitors.

Some of these studies produced durable tumor growth inhibition. Although these DC-based methods are effective, they are also limited by cumbersome procedures and high cost.


In contrast, direct injection of naked mRNA or composite mRNA is considered a fast and efficient feasible method. For example, a phase I/II trial repeated intradermal administration of mRNA vaccines encoding 6 different TAAs ( MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1 ) in 30 patients with metastatic renal cell carcinoma.

Long-term results after 10 years show that the mRNA vaccine is safe and effective. It slowed tumor growth and improved survival, which was strongly correlated with the detected immune response against TAAs.


In another study, 7 patients with locally advanced and 39 patients with metastatic NSCLC received 5 intradermal injections of CV9201 , a protein encoding 5 NSCLC antigens ( NY-ESO-1, MAGE-C1/2, survivin , 5T4 ) live vaccine.

Sixty-three percent of patients developed an antigen-specific immune response against at least one antigen, and 60% showed an increase in activated IgD+CD38high B cells.

Thirty-one percent of patients had stable disease ( SD ), and another two-thirds had progressive disease.

A similar study aimed at boosting antitumor immunity examined CV9202 vaccination combined with local radiotherapy in patients with advanced NSCLC.


CV9202 is a live RNA-based vaccine encoding 6 NSCLC TAAs ( NY-ESO-1, MAGE-C1, MAGE-C2, 5T4, survivin and MUC-1 ). Antigen-specific cellular and humoral immunity was enhanced in most patients compared to baseline. One patient who received vaccine, radiotherapy and chemotherapy experienced a partial response ( PR ) and 46.2% achieved SD.


mRNA-4157 vaccine is an mRNA vaccine developed by Moderna Corporation of the United States. It is an individualized tumor vaccine tailored for each tumor patient. Currently, mRNA-4157 cancer vaccine can accommodate up to 34 mRNA sequences encoding neoantigens.

In a phase I clinical trial of mRNA-4157 in combination with Keytruda, 11 of 13 patients who received monotherapy had stable disease.

In the combination arm, 6 of 20 patients responded, including 1 complete response and 5 partial responses. Six patients had stable disease and eight had worsening disease. All adverse events associated with mRNA-4157 were reversible and mild.

No treatment-related grade ≥3 adverse events were observed, demonstrating the safety and tolerability of the vaccine. Currently, a number of tumor mRNA vaccines are in the clinical recruitment stage.




The CRISPR-Cas9 system is a bacterial defense mechanism that utilizes guide RNA ( gRNA ) to mediate the introduction of site-specific breaks in target DNA by the DNA endonuclease Cas9.

This DNA editing capability enables CRISPR-Cas9 to be used as RNA therapeutics in genome modification by synthesizing sgRNAs for biological and therapeutic applications.


Numerous studies have shown that CRISPR/Cas9 can be used to treat genetic diseases such as cystic fibrosis ( CF ), Duchenne muscular dystrophy ( DMD ), hemoglobinopathies, as well as HIV and beta-thalassemia.

In one study, CRISPR/Cas9 was able to increase the amount of utrophin in myotubes and remove repetitive DMD exons 18–30 to generate full-length dystrophin in DMD.


In beta-thalassemia, mutations in the human hemoglobin beta ( HBB ) gene can be corrected by CRISPR/Cas9. Via the piggyBac transposon, CRISPR/Cas9 in patient-derived IPSCs efficiently corrected HBB mutations without affecting IPSC pluripotency and restored HBB expression upon differentiation into erythrocytes. In addition, similar applications of CRISPR-Cas9 have also been demonstrated in immune diseases such as AIDS.


Although these studies provide the basis for future CRISPR-Cas9 clinical trials, several challenges remain to be addressed before CRISPR/Cas9 is further used in clinical trials and subsequent therapy.

Including possible off-target effects of gene editing tools delivered to target cells. In addition, ethical issues and germline applications of CRISPR-Cas9 need to be considered before translating CRISPR-Cas9 into therapeutic applications.




In recent years, RNA-based therapy has gradually emerged as a potential intervention strategy for various diseases.

Generally speaking, RNA therapeutics are divided into different categories based on their mode of action and the molecules used. Many RNA therapeutics have been developed for various diseases and obtained very promising results in many preclinical and clinical studies, especially mRNA vaccines have become one of the hottest research fields.

At present, there are still many obstacles to RNA-based therapy, and many aspects, including delivery systems, still need further research and development.

However, it is undeniable that the next decade belongs to the era of RNA therapy.





1. RNA Therapeutics – Research and Clinical Advancements. Front Mol Biosci. 2021; 8: 710738.

2. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat RevDrugDiscov. 2021 Aug 25 : 1–22.

3. Clinical and immunological effects of mRNA vaccines inmalignant diseases. Mol Cancer. 2021 Mar 15;20(1):52.

Will RNA therapy play the more important role in future?

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.