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Global Translational Medicine Small RNA therapy for pancreatic cancer

O-Me) modifications mimic the biophysical characteristics enable precise delivery of chemotherapeutic agents to
of the 2’-hydroxyl (2’-OH) group, which stabilize siRNAs tumor cells while minimizing toxicity to healthy tissues
against RNases while preventing activation of innate and cells. Similarly, antibody-oligonucleotide conjugates
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immune receptors. Consequently, nearly all therapeutic (AOCs) have also been shown to facilitate the targeted
siRNAs in clinical trials incorporate either 2’-F or 2’-O-Me delivery of oligonucleotides to specific tissues and cells,
modifications. 97 expanding their therapeutic applications beyond the
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Moreover, RNA drugs can now be actively delivered to liver. These molecules consist of an antibody linked to
target cells or tissues through encapsulation or formulation an oligonucleotide through a linker, offering a flexible and
with specific materials, as well as through viral vectors, customizable approach. The antibody targets a cell type of
plasmid DNAs, or intact cells. 98-101 interest specifically, which enables the oligonucleotide to
reach and regulate a disease-associated gene.
Advancements in nanotechnology and materials
science provide promising solutions to the challenges of In 2019, Avidity launched the first AOC drug, AOC 1001,
oligonucleotide drug delivery, particularly in facilitating a transferrin receptor 1 (TfR1)-targeted mAb conjugated
intracellular delivery across biological barriers and with anti-myotonic dystrophy type 1 (DM1) protein kinase
membranes. Key advantages of nanoparticle drug delivery siRNA for the treatment of DM1, which entered Phase I
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systems include the ability to customize biophysics and clinical trials in November 2021. Recently, Avidity’s
biological properties for precise delivery. RNA-delivering AOC drug, AOC 1044, a TfR1-targeted mAb for DMD
nanoparticles can be synthesized in various forms. disease with anti-DMD phosphorodiamidate morpholino
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One strategy involves encapsulating RNA inside lipid oligomer, received FDA fast track and orphan drug status,
bilayers with a positively charged surface, forming lipid further boosting the enthusiasm for AOC development.
nanoparticles that protect RNA and extend its half-life. AOCs are typical combinatorial innovations and have
Patisiran is an example of an RNA drug utilizing this lipid great potential in the future.
nanoparticle-based delivery system, and many other RNA 5. Development of small RNA drugs for PC
drugs in clinical trials employ similar formulations for
delivery. Another approach involves blending negatively To date, two clinical trials of siRNA-based therapies
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charged RNAs with positively charged polymers. Since for PC have been reported. The first therapy, siG12D-
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the liver is the primary organ responsible for filtering LODER, is a biodegradable polymer matrix containing
nanoparticles, a significant portion of nanoparticle-based siRNA targeting KRAS G12D, a mutation in KRAS gene.
RNA therapies has been designed to target liver-related siG12D-LODER has been studied in a dose-escalation
diseases. 104 Phase I trial involving 15 patients, showing a high safety
and tolerability profile, with no instances of dose-limiting
A prominent approach for RNA drug delivery 110
involves the use of conjugates. By binding to specific toxicity. In 2018, this study advanced to a Phase 2 clinical
trial to evaluate the response rate of siG12D-LODER
receptors on cell surfaces, conjugates facilitate the
targeted delivery of covalently attached RNA molecules. in patients with unresectable or borderline resectable
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A well-known conjugate in RNA therapy is GalNAc, PC. The second therapy, CALAA-01, was developed to
which specifically targets the hepatocyte-specific inhibit tumor growth and/or shrink tumors. CALAA-01
asialoglycoprotein receptor. Givosiran, based on contained a siRNA that can suppress the expression of the
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GalNAc conjugate technology, is the first FDA-approved M2 subunit of ribonucleotide reductase, thereby reducing
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RNA drug. Compared to nanoparticle-based delivery tumor growth. In particular, the CALAA-01 siRNA was
systems, conjugate-based delivery requires fewer excipient encapsulated in a stabilized nanoparticle to shield it from
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materials, thereby reducing the risk of toxicity. With the nuclease degradation (Table 5).
continuous development of new technologies, microrobots In addition to siRNA, the therapeutic use of ASO
also hold significant potential for the delivery system of and miRNA mimics has also been developed for cancer
small RNA drugs. 106 treatment, including PC. AZD9150 is an ASO drug that
has been under clinical investigation for patients with
4.5. Other emerging topics in small RNA drugs advanced solid tumors. In August 2024, it completed its
Monoclonal antibodies (mAbs) are well-established Phase 2 clinical trial, demonstrating preliminary anti-
therapeutic agents due to their high specificity and tumor activity. INT-1B3 is a lipid nanoparticle-formulated
sensitivity to extracellular targets. They have also been miRNA (miR-193a-3p) mimic developed for therapeutic
employed in the targeted delivery of small-molecule drugs, intervention in oncology. Pre-clinical work suggested
as demonstrated by antibody-drug conjugates, which that the mechanism of action of INT-1B3 involves

Volume 4 Issue 2 (2025) 24 doi: 10.36922/gtm.8247