Breakthrough! Recent Advances in New Drug R&D of RNA Small Molecule Therapies in the Field of Rare Diseases
Most rare diseases are monogenic disorders, characterized by low incidence, complex etiology, and a lack of effective treatments. The majority of patients have long faced the dilemma of “no cures available and no medicines accessible,” enduring both physical and psychological suffering.
As an important branch of gene therapy, small-molecule RNA therapies have achieved rapid breakthroughs in rare disease treatment in recent years, thanks to their core advantages including precise targeting, clear mechanisms of action, and relatively short R&D cycles. They have become a key force in breaking the deadlock in rare disease care.
By specifically regulating gene expression and intervening in disease progression at the source, RNA therapies include various modalities such as small interfering RNA (siRNA), antisense oligonucleotides (ASO), and RNA editing drugs. They have delivered milestone outcomes in hemophilia, familial chylomicronemia syndrome, rare neurological disorders, and other fields, bringing new hope for survival to rare disease patients worldwide.
Targeted Indications Accelerate in R&D, Multiple New Drugs Approved and Launched
In recent years, global clinical trials of small‑molecule RNA therapies for rare diseases have continued to advance, covering rare diseases in hematological, neurological, metabolic and other systems.Multiple new drugs have been successfully approved and launched, while a large number of drug candidates have entered late‑stage clinical development.With fruitful R&D achievements, these therapies are gradually filling the gaps in the treatment of rare diseases.
I Rare Neurological Diseases: Breaking Delivery Barriers and Exploring New Pathways
Rare neurological diseases have long been a major challenge in RNA small molecule therapy development, due to the existence of the blood–brain barrier, which greatly complicates drug delivery.In recent years, significant progress has been made in this field, especially clinical breakthroughs in RNA editing drugs, bringing new directions for the treatment of rare neurological diseases.
The circular RNA aptamer (ds cRNA) developed by the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences provides a novel strategy for the treatment of Alzheimer’s disease.Animal studies have shown that AAV mediated delivery of ds cRNA reduces amyloid plaques and phosphorylated Tau deposition in the hippocampus of Alzheimer’s disease mice, and decreases neuronal loss by approximately twofold.A single administration achieves therapeutic effects lasting at least six months, improves spatial memory in mice, and shows no significant toxicity[1]. This achievement opens a new avenue for the development of RNA small molecule therapies for Alzheimer’s disease and demonstrates broad clinical application prospects.
In addition, RNA-based small-molecule drugs for neurodegenerative rare diseases such as Huntington’s disease and amyotrophic lateral sclerosis (ALS) are also under active clinical development, focusing on the optimization of blood–brain barrier shuttle technologies to address delivery challenges.
Among them, SKY-0515, an oral RNA splicing modulator developed by Kyhawk Therapeutics, has shown outstanding potential.Phase I clinical data over 9 months demonstrated that SKY-0515 can cross the blood–brain barrier and dually target disease‑causing genes, leading to favorable improvements in patients’ clinical scores.The drug has advanced into a pivotal global multicenter Phase II/III clinical trial and is expected to become a best‑in‑class therapy for Huntington’s disease [2].
The recently released 9‑month interim data from the Phase I clinical trial made SKY‑0515 a standout:In 17 treated patients (pooled analysis of 4 mg and 9 mg doses), scores on the comprehensive Unified Huntington’s Disease Rating Scale (cUHDRS) continued to improve.At 9 months, scores improved by an average of 0.64 points from baseline, whereas untreated patients were projected to decline by 0.73 points — a difference of more than 1.3 points, marking a breakthrough in reversing the natural history of the disease.
Meanwhile, the 9 mg dose reduced mHTT protein levels by 62% in patient blood, and PMS1 mRNA levels decreased in a dose‑dependent manner by 26%.The drug was generally safe and well‑tolerated, with no serious adverse events reported [2].
SKY‑0515 is now in a pivotal global multicenter Phase II/III clinical trial (NCT06873334) and is poised to become a best‑in‑class disease‑modifying therapy for Huntington’s disease.
II Rare Hematological Diseases: Breaking the Limitations of Traditional Treatments
Hemophilia, a typical rare hematological disease, has long relied on regular coagulation factor injections for traditional treatment, which is associated with drawbacks such as short half-life, frequent administration requirements, and the development of inhibitors in some patients.
The emergence of RNAi therapy has completely transformed the treatment landscape of hemophilia, with 2025 marking a pivotal breakthrough year in this field: In March, the U.S. FDA approved the RNAi new drug Qfitlia (fitusiran) for the prevention of bleeding in patients aged 12 years and older with hemophilia A or B, regardless of the presence of coagulation factor inhibitors. By targeting and silencing the mRNA of the SERPINC1 gene to inhibit antithrombin production, the drug achieves an administration frequency of once every two months, significantly reducing the treatment burden on patients.
In December, the National Medical Products Administration (NMPA) approved fitusiran (brand name: Saifeiyin), an RNAi therapy from Sanofi, for marketing.It is the world’s first RNA interference therapy for hemophilia.With only 6 injections per year, it effectively prevents bleeding in patients with severe hemophilia.
Its Phase III clinical trial data showed that for refractory patients with inhibitors, the annualized bleeding rate was reduced from 18.1 to 1.7 episodes, representing a 90.8% reduction in bleeding.Some patients achieved zero bleeding events.
Fitusiran Sodium Injection Approved by NMPA for Marketing
III Rare Metabolic Diseases: Precise Intervention in Abnormal Lipid Metabolism
Familial Chylomicronemia Syndrome (FCS) is a severe rare metabolic disease. Patients have triglyceride levels 10 to 100 times higher than normal, putting them at high risk of life‑threatening acute pancreatitis, with no effective treatments previously available.
In November 2025, the U.S. FDA approved REDEMPLO (plozasiran), an siRNA drug developed by Arrowhead Pharmaceuticals, for marketing.It is the first FDA‑approved siRNA drug for FCS.
By targeting the APOC3 gene and inhibiting apolipoprotein C‑III production, it accelerates the breakdown and clearance of triglycerides.Patients only need one subcutaneous injection every three months to effectively control the condition and significantly reduce the risk of acute pancreatitis.The drug can be self‑administered at home, greatly improving treatment convenience.
Furthermore, in the field of primary hyperoxaluria type 1 (PH1), two siRNA drugs have already been approved:lumasiran (Oxlumo) by Alnylam and nedosiran (Rivfloza) by Novo Nordisk.
Both reduce oxalate production at the source and slow disease progression by silencing specific target genes.The approval of these two agents has created healthy competition and further improved patient access to treatment.
IV Other Areas: Multi‑Point Breakthroughs Covering More Rare Disease Subtypes
Beyond the above areas, small‑molecule RNA therapies continue to advance in rare diseases such as hereditary transthyretin‑mediated amyloidosis (ATTR) and acute hepatic porphyria.
In the ATTR field, Amvuttra, an siRNA drug from Alnylam, has been expanding its indications.In March 2025, it was approved by the U.S. FDA for the treatment of ATTR‑CM (cardiac amyloidosis), following its earlier approval for ATTR‑PN (polyneuropathy).It has become the first RNAi drug indicated for both major subtypes of ATTR.Its key advantages include a longer dosing interval and better patient compliance.
In acute hepatic porphyria, Alnylam’s givosiran (Givlaari) has been the only newly approved drug in recent years.With consistent efficacy, it has achieved steady sales growth, reaching $2.56 billion in 2024, a 24% year‑over‑year increase.It provides the only targeted therapy for patients living with this ultra‑rare disease.
Furthermore, in the field of primary hyperoxaluria type 1 (PH1), two siRNA drugs have already been approved:lumasiran (Oxlumo) by Alnylam and nedosiran (Rivfloza) by Novo Nordisk.
Both reduce oxalate production at the source and slow disease progression by silencing specific target genes.The approval of these two agents has created healthy competition and further improved patient access to treatment.
Image source: Reference [4]
[1].Feng X, Jiang BW, Zhai SN, et al. Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models. Nat Biotechnol. Published online March 31, 2025. doi:10.1038/s41587-025-02624-w
[2]. https://www.skyhawktx.com/
[3]. Awaya T, Ajiro M, Kobayashi H, et al. Invention of an oral medication for cardiac Fabry disease caused by RNA mis-splicing. Sci Adv. 2025;11(15):eadt9695. doi:10.1126/sciadv.adt9695
[4]. https://investors.alnylam.com/press-release?id=28831