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Global Translational Medicine Small RNA therapy for pancreatic cancer

Table 5. (Continued)
Number Clinical trial Type Drug candidate name Target name Targeted disease Status
number
39 NCT03373786 miR-21 RG-012 miR-21 Alport syndrome Phase 1
inhibitors
40 NCT03713320 miR-155 Cobomarsen miR-155 CTCL and MF subtype Phase 2
41 NCT04675996 miR-193a-3p INT-1B3 Unknown Advanced solid tumors Phase 2
42 NCT02508090 miR-122 Miravirsen miR-122 Hepatitis C virus Phase 2
inhibitors
43 NCT05953831 miR-132 CDR132L miR-132 Heart failure Phase 2
inhibitors
Source: Data obtained from https://clinicaltrials gov.
Abbreviations: siRNA: Small interfering RNA; ASO: Antisense oligonucleotide; RRM2: Ribonucleotide reductase regulatory subunit M2;
HIF2α: Hypoxia-inducible factor 2 alpha; MYC: MYC proto-oncogene; AGT: Angiotensinogen; HBV: Hepatitis B virus; ANGPTL3: Angiopoietin-like 3;
PCSK9: Proprotein convertase subtilisin/kexin type 9; ADRB2: Adrenoceptor beta 2; TGF-β1: Transforming growth factor beta 1;
COX-2: Cyclooxygenase-2; CTGF: Connective tissue growth factor; KRAS G12D: Kirsten rat sarcoma viral oncogene homolog with G12D mutation;
AT3: Antithrombin III; LDHA: Lactate dehydrogenase A; TTR: Transthyretin; TRPV1: Transient receptor potential vanilloid-1; C9orf72: Chromosome
9 open reading frame 72; STAT3: Signal transducer and activator of transcription-3; BCL-2: B-cell lymphoma 2; CEP290: Centrosomal protein 290;
APOC3: Apolipoprotein C3; HTT: Huntingtin; NASH: Nonalcoholic steatohepatitis; HCC: Hepatocellular carcinoma; AMD: Age-related macular
degeneration; ATTR-CM: Transthyretin amyloid cardiomyopathy; CTCL: Cutaneous T-cell lymphoma; MF: Mycosis fungoides.

effectively suppress proprotein convertase subtilisin/kexin more clinical data are needed to assess the long-term risks
type 9 gene expression, resulting in sustained reductions associated with these modifications. Further advancements
in low-density lipoprotein cholesterol levels for up to in RNA therapeutics will depend on improvements in
6 months post-treatment. This long-lasting effect is RNA design, the development of more efficient delivery
87
particularly beneficial for patients who may not undergo systems, and the refinement of targeted technologies to
frequent treatments. ensure therapeutic efficacy while minimizing off-target
effects and immunogenicity.
Despite these advantages, small RNA drugs also have
three key disadvantages. First, targeted delivery remains 4.4. Chemical modification and delivery of small
a major challenge. However, significant progress has RNA drugs
been made in developing various delivery platforms.
Evidence from recently approved RNA-based drugs and A significant challenge in developing RNA-based drugs
ongoing clinical trials suggests that RNA therapies can is preventing degradation by serum RNases while
be delivered to the liver with high efficiency. However, enabling RNA molecules to cross the membranes of target
cells, ensuring sufficient intracellular delivery to elicit
effective delivery to non-liver tissues and organs remains
a significant challenge. Future research will need to focus pharmacological effects. Certain chemical modifications
on developing strategies to enhance RNA delivery to these can greatly enhance the metabolic stability and
pharmacokinetic properties of RNA,
making them
90,92-94
targeted tissues.
more viable as drug candidates.
Second, the synthesis and purification of small RNA
drugs are complex and costly. The need for chemical Modifications to the phosphate backbone, ribose
modifications and specialized delivery systems further ring, and 3’- and 5’-ends of RNA can improve substrate
specificity, enhance nuclease resistance, and facilitate
increases manufacturing expenses, making RNA drugs targeted delivery. In addition, these modifications can
among the most expensive medications on the market. 88,89 reduce toxicity and immune responses. The modification
95
While automation has improved the chemical synthesis and of the phosphorothioate backbone was the first widely
purification processes, the production of large quantities of adopted modification in ASOs, in which one of the non-
synthetic RNA for animal studies, clinical trials, and large- bridging oxygen atoms in the internucleotide phosphate
scale medical use remains logistically and economically group is replaced with sulfur. This modification increases
96
challenging. the hydrophobicity of ASO molecules, enhances resistance
Third, artificial modifications of RNA raise concerns to phosphodiesterases, improves cellular uptake, and
regarding their impact on RNA folding, activity, and safety strengthens binding to serum proteins, thereby improving
compared to naturally occurring RNA. 90,91 At present, bioavailability. The 2’-fluoro (2’-F) and 2’-O-methyl (2’-
96

Volume 4 Issue 2 (2025) 23 doi: 10.36922/gtm.8247