Small Nucleic Acid Drugs Enter a New Era, Onto Bio: Pioneering Antisense Upregulation Technology Opens a New Chapter in Cures | Gaorong Future

In recent years, RNA-targeted therapies and small nucleic acid drugs have attracted significant attention for their high specificity and curative potential. The core logic of RNA therapeutics is to use artificially designed nucleic acid molecules (such as ASOs and siRNAs) to target RNA inside cells (primarily mRNA) and modulate its expression, acting upstream of protein translation to intervene in and treat disease.

Arnatar, founded in 2022 by a world-class team of scientists in nucleic acid therapeutics, focuses on novel antisense nucleic acid technology and RNA-targeted drug development.

The company has built the proprietary breakthrough dual-modal nucleic acid drug platform DARGER™, enabling Arnatar to pursue two parallel paths and develop two classes of RNA drugs: on one hand, through best-in-class siRNA gene silencing technology to silence disease-causing genes; on the other, by innovatively integrating the world's first protein expression upregulating antisense oligonucleotide (ASO) technology to restore critical protein function, opening entirely new therapeutic avenues for previously untreatable diseases.

Arnatar's R&D pipeline covers cardiovascular and metabolic diseases, liver, kidney, and central nervous system disorders, focusing on areas of high unmet medical need, including both common and rare diseases.

Gaorong Ventures participated in Arnatar's Series A financing in 2024. Recently, Dr. Xuehai Liang, founder and CEO of Arnatar, shared Arnatar's unique antisense nucleic acid technology and innovative drug development strategy at a biopharma innovation Demo Day co-hosted by Gaorong Ventures and PwC. Arnatar is currently advancing its Series B financing.

Dr. Xuehai Liang is a renowned expert in RNA-targeted therapeutics with over 25 years of experience in antisense nucleic acid technology innovation, having previously held R&D leadership positions at Ionis, a pioneer in ASO therapeutics.

Innovative Antisense Nucleic Acid Technology Enabling Protein Expression "Upregulation"

Mutations or abnormal expression of RNA frequently cause disease. Antisense nucleic acid molecules can be designed to specifically target RNA to modulate its function and protein expression, enabling personalized drug design. The success and approval of more than ten antisense drugs in recent years heralds the arrival of the RNA-targeted therapy era.

Among these, antisense oligonucleotides (ASOs) are artificially synthesized short-chain nucleic acid molecules (typically 15-30 nucleotides in length). As "precision drug tools," they can regulate gene expression through various mechanisms — both "silencing genes" and "upregulating genes."

Dr. Liang notes, "When people think of small nucleic acid drugs, they tend to think of downregulation, reducing protein expression; Arnatar has successfully developed an entirely new path in the opposite direction — using ASOs to increase protein expression."

Many diseases (including liver, kidney, and central nervous system disorders) are caused by haploinsufficiency, where one normal allele cannot produce sufficient protein.

The translation of mRNA into protein involves mRNA carrying genetic information into the cytoplasm, where ribosomes scan and locate the start codon to begin translation. "This process is a rate-limiting step in protein translation, which creates room for regulation — using ASOs to target specific mRNA to enhance translation efficiency, thereby increasing protein expression without altering mRNA levels."

Dr. Liang explains that Arnatar's ASO upregulation technology, ACT-UP1, is uniquely designed with two functional domains. One is a traditional ASO that targets specific mRNA through base pairing; the other is that ACT-UP1 ASOs can recruit proteins required for efficient translation initiation within cells, effectively "activating" the targeted mRNA to enhance its translation efficiency and achieve increased levels of specific proteins — this is Arnatar's core technology.

Dr. Liang points out, "Using this technology, Arnatar has explored dozens of different targets, with excellent protein expression enhancement effects. Theoretically, ACT-UP1 ASOs can target any target, provided only that a functional mRNA exists in the cell. This significantly broadens the therapeutic landscape with very high specificity."

Beyond its unique ASO upregulation platform, Arnatar also possesses ultra-high-activity siRNA technology capable of gene silencing. Building on these platforms, Arnatar has established a pipeline of FIC (first-in-class) and BIC (best-in-class) programs in both downregulation and upregulation directions.

Arnatar's Dual-Modal Nucleic Acid Drug Platform DARGER™

The ability to rapidly build this technology platform within three years stems from the core team's extensive industry experience. Founding team members previously held R&D leadership positions at Ionis, a pioneer in ASO therapeutics. The team also includes seasoned experts with years of experience in RNA biology, drug target selection, and small nucleic acid chemical synthesis.

Two ASO Protein-Upregulation Pipelines Show Excellent Progress

To date, Arnatar's two ASO protein-upregulation pipelines developed on its platform have achieved remarkable progress. The protein-upregulation candidate ART4 for Alagille syndrome (ALGS) completed first-patient dosing in its IIT clinical trial in September 2025, and received FDA Orphan Drug and Rare Pediatric Disease designations, highlighting its potential as a transformative therapy. A New Drug Application (IND) is expected to be submitted in January 2026.

The protein-upregulation candidate ART5 for autosomal dominant polycystic kidney disease (ADPKD) demonstrated preclinical potential to reverse cyst formation, with IND submission expected in early Q2 2026.

Protein-Upregulation Candidate ART4: Treating Disease at Its Root

ART4 is developed based on Arnatar's ACT-UP1 technology, treating Alagille syndrome (ALGS) through ASO-mediated protein upregulation. ALGS is a rare, life-threatening multi-system disease primarily affecting the liver, heart, and kidneys. The disease mechanism is well understood: approximately 95% of ALGS cases are caused by haploinsufficiency mutations in the Jagged-1 (JAG1) gene, resulting in insufficient JAG1 protein levels — half or less than healthy individuals — leading to abnormal bile duct development, elevated bile acid levels, and subsequent liver damage and other organ injury.

Currently, no effective treatments exist for this disease. The approved small molecule drug Maralixibat oral solution is indicated for pruritus as an endpoint, offering no benefit to damaged organs.

ART4 has the potential to become the first effective treatment targeting the fundamental cause of ALGS by increasing protein expression through ASO, achieving a leap from "symptomatic treatment" to "disease-modifying therapy."

According to preclinical studies, in ALGS mouse models, diseased mice expressed functional JAG1 protein at half the level of normal mice. Through subcutaneous ART4 administration once weekly for three doses, JAG1 protein increased by 40% within one month, with concurrent restoration of bile duct development and significant improvement in liver function (bile acid levels decreased by over 40%, with improvements in both alanine aminotransferase ALT and aspartate aminotransferase AST levels). Dr. Liang notes, "This proves that ART4's technical approach is correct — reduced JAG1 protein is indeed the true cause of disease; by elevating its protein levels, therapeutic effects can be achieved."

Due to its unique mechanism of action, ART4 offers three differentiated advantages: superior efficacy, better safety, and more convenient administration.

Protein-Upregulation Candidate ART5: Potential to Reverse Cyst Formation

Arnatar's other candidate pipeline, ART5, is for autosomal dominant polycystic kidney disease (ADPKD), a progressive genetic disease with heavy disease burden.

In 2025, Novartis acquired a single-asset kidney disease miRNA drug development company for $1.7 billion; its primary asset, Farabursen, is an ASO targeting microRNA-17 for ADPKD to indirectly increase protein expression. However, because it targets microRNA-17 — which can regulate hundreds of mRNAs — inhibiting microRNA-17 may simultaneously alter many other proteins.

Returning to the pathogenic mechanism: approximately 85% of ADPKD is caused by mutations in the PKD1 gene (encoding PC1 protein), with another 10-15% caused by PKD2 gene mutations. Patients with PKD1 mutations have larger numbers, earlier onset, and more severe symptoms, eventually requiring dialysis or kidney transplantation. Currently, the only available drug is a small molecule inhibitor with significant hepatotoxicity.

ART5 treats ADPKD through specific PKD1 upregulation, with good specificity reducing off-target risk, plus long-acting properties supporting dosing every 1-2 months. Most critically, it has potential to reverse cyst formation.

Dr. Liang explains that in mouse embryonic kidney models, cysts were first artificially induced to mimic disease progression; after ART5 treatment, PC1 protein in cystic kidneys increased by approximately 50%, with significant reduction in cyst numbers. "This result demonstrates, consistent with previous research, that restoring PC1 expression can reverse cyst growth."

From Rare Diseases to Chronic Diseases: Promising Future for ASO Technology

The above two pipelines primarily target rare diseases caused by genetic mutations. Dr. Liang emphasizes that ASO technology has a promising future.

On one hand, diseases caused by haploinsufficiency are widespread. Based on human disease research, approximately 300 or more genes are currently known to carry haploinsufficiency risk. Many haploinsufficiency diseases affect the central nervous system and other organs — for example, SON causes kidney abnormalities and renal developmental defects.

Furthermore, "ACT-UP1 technology can not only treat rare diseases, but also has great potential for many major chronic diseases" — such as metabolic diseases where key proteins gradually decrease without mutation, where ASOs can be used to increase protein levels and intervene in disease progression.

Arnatar's technology blueprint is sketching out the boundless possibilities of the RNA medicine era, driving a paradigm shift in RNA therapeutics from "treating symptoms" to "treating causes," unlocking new chapters of healing through the code of life.