CWON Press

For decades, hypertrophic scars and keloids have largely been treated from the outside in. Silicone products cover the scar. Corticosteroids are injected into it. Lasers remodel its vascularity and collagen. Surgery removes it. A new generation of experimental therapies is attempting something fundamentally different: intervene in the molecular program that creates excessive fibrosis in the first place. Small interfering RNA, or siRNA, is emerging as one of the most promising technologies for this approach. Rather than broadly suppressing inflammation or physically remodeling scar tissue, siRNA can be designed to selectively reduce expression of a gene involved in fibrosis. For hypertrophic scars, one of the most important targets is connective tissue growth factor, also known as CTGF or CCN2. Several RNA-based drug developers have already taken CTGF-targeting therapies into human trials. Among them is South Korea-based Lemonex Inc., which has completed a first-in-human Phase 1 study of LEM-S401, an investigational CTGF-targeting siRNA delivered using the company’s biodegradable DegradaBALL platform. The program raises an important question for the next generation of scar therapy: Can better RNA delivery achieve meaningful antifibrotic activity with substantially less siRNA?

Why CTGF Matters in Scar Formation

Fibrosis is not simply an excess of collagen. It is the result of dysregulated cellular signaling. After tissue injury, fibroblasts become activated and produce extracellular matrix proteins that help repair damaged tissue. Normally, this response eventually subsides. In pathological scarring, however, fibroblasts can remain excessively active. CTGF plays an important role in this process. It interacts with major fibrotic signaling networks, including transforming growth factor beta, and contributes to fibroblast activation, extracellular-matrix production and collagen deposition. Elevated CTGF activity has therefore been implicated in a wide range of fibrotic diseases. In skin, suppressing CTGF offers a conceptually attractive therapeutic strategy: rather than removing excess collagen after it is deposited, reduce one of the signals that drives its production.

How siRNA Changes the Therapeutic Logic

siRNA uses the cell’s natural RNA-interference machinery. A properly designed siRNA enters the cell and guides a protein complex toward a complementary messenger RNA, or mRNA. The target mRNA is then degraded, reducing production of the corresponding protein. For a CTGF-targeting therapy, the objective is straightforward in principle: less CTGF mRNA → less CTGF protein → weaker fibrotic signaling. But the biology is only half the problem. The other half is delivery. RNA molecules are fragile. They can be degraded rapidly by enzymes and have difficulty crossing cell membranes.

An effective RNA medicine therefore requires a mechanism that can:

• protect the RNA;
• retain it at the desired site;
• facilitate cellular uptake;
• release it in a therapeutically useful manner;
• and limit unnecessary systemic exposure.

For localized diseases such as hypertrophic scars, this delivery challenge may be particularly important. The ideal drug does not necessarily need high concentrations throughout the bloodstream. It needs enough RNA in the correct local tissue for long enough to silence the intended target.

The CTGF-siRNA Race Has Already Reached the Clinic

OliX Pharmaceuticals has been one of the pioneers in CTGF-targeting RNA therapy. Its investigational candidate OLX10010 uses a cell-penetrating asymmetric siRNA architecture designed to enter cells without a conventional delivery vehicle.

In its Phase 1 program, OLX10010 was evaluated at doses of:

• 1 mg
• 4 mg
• 10 mg
• 20 mg

The program subsequently progressed into a Phase 2a study in hypertrophic scars following scar-revision surgery. Clinical regimens have included 2 mg/cm and 5 mg/cm administered repeatedly after surgery. The program is important because it provides human clinical evidence that CTGF-directed RNA interference can be practically explored in scar treatment. Earlier programs, including RXI-109, also investigated CTGF-directed RNA approaches for postsurgical scars and keloids. Collectively, these studies helped validate fibrosis-related genes as legitimate targets for RNA therapeutics. But they also highlighted a key development question: How much RNA is actually required at the site of disease?

Lemonex Is Taking a Delivery-Platform Approach

Lemonex Inc. is pursuing CTGF inhibition through a different strategy. Its investigational drug LEM-S401 combines a CTGF-targeting siRNA, LEM-17234, with the company’s DegradaBALL drug-delivery platform. DegradaBALL is a biodegradable porous silica-based delivery system designed to load and locally release therapeutic molecules. The objective is not simply to produce an active siRNA sequence. It is to create a local drug depot capable of retaining the RNA near the administration site and releasing it over time. Results from the first-in-human Phase 1 study of LEM-S401 were published in Clinical and Translational Science in 2025. The randomized, double-blind, placebo-controlled, single-ascending-dose trial enrolled 18 healthy adults. Twelve participants received LEM-S401 and six received placebo.

Three siRNA dose levels were tested:

• 40 μg
• 100 μg
• 200 μg

The siRNA was formulated with DegradaBALL at an siRNA-to-carrier mass ratio of 1:5. The most striking feature of the study is immediately apparent from the dose units. LEM-S401 entered human testing in micrograms, not milligrams.

Phase 1: Safety Comes First

The LEM-S401 Phase 1 trial was not designed to establish clinical efficacy in hypertrophic scars. All participants were healthy adults, and all 18 were men. The study therefore cannot answer whether LEM-S401 reduces cesarean scars, whether it is safe in postpartum women, or whether it can be administered during breastfeeding. Its primary purpose was to evaluate safety, tolerability and pharmacokinetics after a single administration. Within that framework, the results were encouraging. Drug-related adverse events were mainly transient injection-site pain and erythema. No clinically significant abnormalities were reported in vital signs, physical examinations, electrocardiograms or routine laboratory testing. Inflammatory cytokines assessed during the study also did not show significant differences among dose groups. This provides human evidence that the DegradaBALL-siRNA formulation can be administered at the evaluated dose range with generally favorable acute tolerability.

An Important Pharmacokinetic Observation: Minimal Measurable Systemic Exposure

One of the most interesting findings came from pharmacokinetic analysis. Plasma concentrations of LEM-17234 remained below the lower limit of quantification of 1 ng/mL at all measured time points. This result should be interpreted carefully. It does not prove that absolutely no siRNA entered the circulation. But it indicates that measurable systemic exposure was very low under the conditions of the study. For a localized skin-fibrosis treatment, this could be an important characteristic. Unlike systemic RNA therapies designed to reach organs through circulation, a scar therapy may benefit from keeping as much of the active payload as possible near the injection site. In principle, local retention could help reduce unnecessary systemic exposure while maintaining pharmacological activity in the target tissue. Future patient studies will be required to determine whether this translates into meaningful clinical benefit.

Why the Dose Comparison Is So Interesting

The difference between LEM-S401 and some earlier CTGF-siRNA programs becomes particularly visible when absolute siRNA dose is compared.

• LEM-S401 was evaluated at: 0.04 mg, 0.10 mg and 0.20 mg
• OLX10010’s Phase 1 program included: 1 mg, 4 mg, 10 mg and 20 mg

Comparing the highest LEM-S401 dose of 0.2 mg with OLX10010’s 10 mg and 20 mg upper-dose cohorts produces a simple numerical comparison:

• 10 mg ÷ 0.2 mg = 50-fold
• 20 mg ÷ 0.2 mg = 100-fold

In absolute siRNA terms, therefore, the highest LEM-S401 dose was approximately 50 to 100 times lower than the 10–20 mg upper-dose cohorts investigated in the OLX10010 Phase 1 study. That is a meaningful development characteristic. But it is not evidence that LEM-S401 is 50 to 100 times more potent. The two products use different molecular designs, formulations, injection strategies and clinical protocols. They have never been compared in a head-to-head trial. The scientifically appropriate conclusion is more limited: LEM-S401 achieved favorable Phase 1 safety and tolerability at a microgram-level siRNA dose range substantially below the milligram-level doses explored in some previous CTGF-siRNA clinical programs. Whether that low-dose delivery translates into equivalent or superior clinical efficacy remains to be demonstrated. If it does, however, the implications could be considerable.

Why Lower RNA Dose Could Matter

A lower effective RNA dose could potentially offer several advantages.

1. Lower Drug Burden: Using less siRNA may reduce the total quantity of active pharmaceutical ingredient administered per treatment. For a localized therapy requiring multiple injections, this could become clinically relevant.

2. Potentially Lower Systemic Exposure: A delivery system that retains RNA locally may reduce unnecessary distribution beyond the treatment site. This principle is consistent with the very low measurable plasma concentrations observed in the LEM-S401 Phase 1 study.

3. Manufacturing Economics: RNA manufacturing is more expensive and technically demanding than production of many conventional small molecules. If comparable biological activity can ultimately be achieved with substantially less RNA, the difference could influence cost of goods and commercial scalability.

4. Repeat-Treatment Potential: Hypertrophic scar biology evolves over weeks and months. If repeated administration is required, minimizing the dose administered during each treatment could become increasingly important. But this leads to another key question.

DegradaBALL May Be as Important as LEM-S401 Itself

LEM-S401 is being developed as an antifibrotic candidate, but the trial may also be viewed as a human test of a broader delivery concept. RNA therapeutics have historically faced a major limitation: effective delivery outside the liver. Many approved siRNA medicines rely on GalNAc conjugation to achieve highly efficient liver targeting. Lipid nanoparticles have also become prominent, particularly for mRNA vaccines and selected systemic applications. But neither strategy automatically solves the problem of localized and sustained delivery in skin or other peripheral tissues.

DegradaBALL is intended to approach the problem differently. Its porous biodegradable structure is designed to act as a local carrier capable of loading therapeutic molecules and gradually releasing them. For localized diseases, such a depot-style strategy could potentially allow drug developers to use route of administration and local retention — rather than systemic circulation — as part of the targeting mechanism. LEM-S401 therefore has significance beyond scar treatment. It provides clinical evidence that a DegradaBALL-based nucleic-acid formulation can reach human testing. If future studies demonstrate sustained pharmacodynamic activity and therapeutic efficacy, the implications could potentially extend to other localized RNA therapies.

Women with cesarean scars would also need to be specifically studied before any conclusions are drawn about postpartum treatment. These are the studies that will determine whether LEM-S401 becomes a clinically useful antifibrotic drug or remains primarily a proof of concept for a new delivery platform.

From Scar Management to Molecular Medicine

The development of siRNA for hypertrophic scars represents a broader change in medicine. Traditional scar treatment largely focuses on the physical consequences of fibrosis. RNA therapy attempts to intervene upstream.

Instead of only asking: “How can we flatten this scar?” the biological question becomes: “Which molecular signal is causing this tissue to keep producing excessive matrix, and can we turn that signal down?” Together with supportive nonclinical repeat-dose data, those findings create a differentiated development profile. As cesarean delivery becomes increasingly common worldwide, the need for better scar management is likely to grow with it. If future trials show that molecularly targeted RNA treatment can prevent or reduce pathological fibrosis, scar therapy could move beyond silicone sheets, steroid injections and lasers toward something fundamentally different. Not merely treating the scar that remains — but controlling the biology that creates it.

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CWON Press Editorial Note

LEM-S401, OLX10010 and other siRNA products discussed in this article are investigational therapies. LEM-S401 has completed a first-in-human Phase 1 single-dose study in healthy male adults. Cross-trial dose comparisons should be interpreted cautiously because investigational products differ in molecular design, formulation, dosing schedule, administration strategy and study population. A lower absolute dose does not by itself establish greater clinical potency or superiority.

*The lead image at the top of this article illustrates the emerging use of CTGF-targeting siRNA for hypertrophic scars, highlighting clinical RNA programs and how Lemonex’s DegradaBALL® delivery platform is being investigated for localized delivery, microgram-level dosing and low measurable systemic exposure. The lead image was generated using generative AI with ChatGPT.