The field of gene regulation and molecular medicine has witnessed a revolutionary advancement with the development of small interfering RNA (siRNA) therapeutics. Also known as short interfering RNA, siRNA is a class of double-stranded RNA molecules that plays a pivotal role in RNA interference (RNAi)—a cellular mechanism that enables gene silencing. Today, siRNA therapy is gaining traction across various therapeutic areas, offering a precise approach to tackle diseases at the genetic level. 

Small interfering RNA (siRNA) has been deemed a promising therapeutic method for treating diverse diseases. By specifically targeting and post-transcriptionally silencing disease-causing genes, siRNA-based therapies offer a unique mode of action.Usually double-stranded RNA molecules, these tiny interfering RNAs are 21–23 nucleotides long and intended to complement the target mRNA sequence. Therefore, without inducing the creation of interferon, these siRNAs can inhibit the expression of certain genes in mammalian cells. In the study of gene regulation and molecular biology, siRNA medications have become a promising class of treatments. These little RNA molecules have the ability to attach to messenger RNAs (mRNAs) and either cause their breakdown or obstruct their translation into proteins, which regulates gene expression.

In real-world applications, both drug delivery and manufacturing pose significant challenges. Ensuring that a drug reaches its intended site at the right concentration is rarely straightforward. These difficulties are even greater in the case of siRNA therapies due to their unique characteristics. One of the main hurdles in siRNA drug development has been finding effective delivery strategies. Achieving efficient cellular uptake and delivery is essential for these therapies to be successful. Various delivery systems—such as lipid nanoparticles, viral vectors, and conjugated molecules—have been investigated to improve siRNA stability, uptake by cells, and target precision.

Despite these obstacles, a few siRNA-based drugs have received regulatory approval, providing clearer insights into the strengths and limitations of this treatment approach. Research in this field is ongoing, with continued efforts to enhance the specificity, durability, delivery mechanisms, and safety of siRNA therapeutics. In recent years, the small interfering RNA (siRNA) therapeutics market has grown substantially, driven by regulatory approvals, advances in siRNA technology, and increasing investments from biotech and pharmaceutical companies.

Small Interfering RNA Mechanism of Action

siRNA drugs primarily function by silencing specific genes through the RNA interference (RNAi) pathway. This natural process begins in the cytoplasm, where the enzyme Dicer, an endoribonuclease, processes longer double-stranded RNA (dsRNA) or short hairpin RNA (shRNA) into smaller, mature siRNA fragments. These siRNA molecules are typically 21–23 nucleotides in length and feature two phosphorylated overhanging bases at the 3′ end of each strand.

Once formed, the siRNA is loaded into the RNA-induced silencing complex (RISC), a multi-protein assembly that includes key components such as Dicer and Argonaute-2 (Ago-2). Within this complex, the siRNA is unwound into two strands: the sense (passenger) strand and the antisense (guide) strand. The sense strand is discarded, while the antisense strand remains bound to RISC and guides the complex to its complementary target mRNA. When the antisense strand binds to its matching mRNA sequence, the Ago-2 protein cleaves the mRNA, thereby preventing gene expression.

The siRNA pathway involves the following steps:

1. Delivery of siRNA into the cell, often via nanoparticles or conjugated carriers.
2. Unwinding of the siRNA duplex, with the guide strand integrating into the RNA-induced silencing complex (RISC).
3. Target recognition, where the RISC–siRNA complex identifies complementary mRNA.
4. mRNA cleavage, which halts protein translation, effectively silencing the gene.

This process is also referred to as RNAi interference or RNAi therapeutics, and it distinguishes itself from other gene therapies due to its transient, reversible, and highly specific nature. In therapeutic applications of RNAi, the Dicer processing step can be bypassed by directly delivering synthetically produced siRNAs. Since the effectiveness of the RNA-induced silencing complex (RISC) is governed by the guide (antisense) strand, careful design of this strand is essential to ensure both high specificity and strong gene-silencing activity. It’s not only crucial for the antisense strand to be fully complementary to the intended mRNA target, but also to avoid partial matches that could cause unintended gene silencing. Even a short, 7-nucleotide match within the seed region of the antisense strand can be sufficient to activate RISC and cause off-target effects. To minimize such risks, computational tools like NCBI BLAST can be used to identify unique and specific target sequences within the human transcriptome.

Therapeutic Applications of SiRNA

Designing siRNA for Cancer Therapy

RNA interference (RNAi) is a gene-silencing mechanism used to target oncogenes and tumor-specific biomarkers. In recent years, siRNA has gained significant traction for clinical applications. For instance, Patisiran, an siRNA-based therapy, is approved for treating amyloidotic polyneuropathy by silencing the Transthyretin (TTR) gene, while Givosiran targets δ-aminolevulinate synthase 1 (ALAS1) to treat acute hepatic porphyria. In the field of oncology, siRNA-based treatments such as siG12D-LODER, which targets KRAS mutations in pancreatic cancer, and TKM-PLK, designed to silence polo-like kinase 1 in solid tumors, have shown encouraging outcomes in clinical trials. Further siRNA therapy showed improved therapeutic efficacy and reduced resistance when used in combination with chemotherapy and immunotherapy.

For instance, a preclinical study demonstrated that blocking STAT3 using locally delivered CpG-STAT3 siRNA significantly improved the efficacy of immune checkpoint inhibitors in B-cell lymphoma and melanoma models. Another study demonstrated that Survivin siRNA with neoadjuvant chemotherapy (paclitaxel or epirubicin) showed significant apoptosis and improved drug sensitivity in MCF-7 breast cancer cells.

Naked siRNA-Based Therapeutics

Naked siRNA therapeutics refer to small interfering RNA molecules delivered without the use of any carrier system. In contrast to delivery methods that rely on lipid nanoparticles or viral vectors to improve stability and facilitate cellular entry, naked siRNA is administered directly into the body without encapsulation or complex formation. Common routes of administration include injection and inhalation. While this approach is relatively simple and more cost-effective, it is hindered by several limitations that affect its overall therapeutic effectiveness.

Some of the examples are: QPI-1002 (teprasiran or I5NP) is a naked siRNA therapeutic developed by Quark Pharmaceuticals. It targets the p53 gene, which plays a role in acute kidney injury (AKI). Demirjian and co-workers described using intravenous administration of QPI-1002 in a Phase I study. SYL040012 (bamosiran) is a naked siRNA-based therapeutic developed by Sylentis (PharmaMar Group). This is the first therapeutic siRNA used for eye treatment. The gene of vascular endothelial growth factor receptor 1 (VEGFR1) is targeted to inhibit angiogenesis in ocular maladies, including age-related macular degeneration (AMD) and diabetic macular edema (DME). 

Quark Pharmaceuticals developed QPI-1007 to treat ocular diseases. Specifically, QPI-1007 targets the gene responsible for producing caspase 2, an enzyme involved in cell death pathways to prevent apoptosis. The drug is being developed for various ocular disorders, namely non-arteritic anterior ischemic optic neuropathy (NAION), primary open-angle glaucoma (POAG), and DME.

Regulatory Landscape

FDA and EMA Approval Pathways

The regulatory environment for siRNA therapeutics is evolving in response to the rapid growth of RNA-based technologies. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adapted existing frameworks to accommodate the unique properties of siRNA therapies. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in Europe are the regulatory bodies in charge of overseeing medications that have already received approval in the US and the EU, respectively, and assessing applications for marketing authorization. Clinical and non-clinical guidelines on quality issues are periodically released by both bodies.

The initial discovery of the new medication and proof of its safety and effectiveness in animal models and cell cultures are included in the preclinical phase. This is necessary to determine the drug’s mechanism of action and assess how well it works against the intended ailment. Studies on siRNA-containing nanoparticles should also assess any possible off-target effects as well as siRNA-mediated immunological or inflammatory reactions.

The new medication will enter the clinical trials phase, which is divided into phases I, II, and III, after receiving IND approval. The new drug’s safety profile will be examined in these studies, and the advantages of the new treatment over current ones will be ascertained. Lastly, a New Drug Application (NDA) will be submitted to the regulatory body if the new drug is found to be safe and effective. The regulatory body will review the NDA and may request more information or approve it, either with or without requesting additional post-marketing data like phase IV or post-marketing studies.

Guidelines for RNA Therapeutics

As of right now, siRNA-containing nanoparticles are not subject to any special regulations. However, as a guide for the development of human drug products, including biological products where a nanomaterial is a component of the dosage form, the FDA released the document “Drug Products, Including Biological Products, that Contain Nanomaterials” in 2018.

Unless the kind and design of the RNA therapeutic warrants a different approach, EMA recommends that biodistribution studies be conducted for RNA therapies. Additionally, the FDA recommends doing biodistribution studies, but only for novel vector classes and in cases where there are substantial modifications to vector backbones, formulations, administration methods, dose levels, and dosing regimens. 

• The analytical techniques that are used in preclinical studies of RNA therapeutics should be validated.Applicants must demonstrate that the used techniques, procedures, equipment, and materials are appropriate to detect the target (i.e., the RNA product, a carrier component, or the expressed protein) at the molecular level and in the relevant biological matrix. This can be demonstrated either through own experimental data or by referring to published data. Guidelines on validation of analytical techniques are available from multiple agencies.
• The chosen animal species used in preclinical studies on RNA therapeutics should be as biologically relevant as possible and show a pharmacological response that is similar to the expected response in humans.
• FDA and ICH advise to use at least 5 animals per sex per group per sacrifice timepoint for rodents and correspondingly 3–5 animals for non-rodents. EMA does not specify numbers in their guidelines, nor does WHO in the vaccine guidelines. Remarkably, this is in contrast with WHO guidelines for toxicology, which advise to use 10 rodents per sex and per experimental group.
• The minimal panel of tissues to be examined mainly depends on the RNA product, the expressed protein, and the route of administration. However, prespecified tissue panels have been determined and can be used as a general starting point

Recent Advancements and Pipeline Overview

The field of siRNA therapeutics is witnessing remarkable momentum, driven by clinical successes, technological innovation, and increasing investor and pharmaceutical interest. Since the approval of the first siRNA drug, Patisiran (Onpattro) in 2018 for hereditary transthyretin-mediated amyloidosis, the pipeline has expanded to include multiple clinical-stage candidates targeting a wide range of diseases.

siRNA Drugs in Clinical Trials

Several siRNA therapies are currently in clinical development, aiming to address both rare and prevalent diseases:

• Inclisiran (Leqvio), developed by Novartis (originally discovered by Alnylam and The Medicines Company), is approved both in the EU and the United States. It received EU approval in December 2020 and FDA approval in December 2021 for lowering LDL cholesterol by targeting PCSK9 mRNA. The FDA expanded inclisiran’s indication in July 2023 to include adults with primary hypercholesterolemia and those at increased risk of heart disease, enabling broader use beyond just familial hypercholesterolemia or ASCVD. It is currently marketed as a subcutaneous injection dosed twice a year following initial doses
• Vutrisiran (Amvuttra), another Alnylam product, is an enhanced version of Patisiran, offering subcutaneous dosing for transthyretin amyloidosis.
• Zilebesiran targets angiotensinogen (AGT) for hypertension and is being evaluated in Phase II trials.
• ARO-HSD from Arrowhead Pharmaceuticals targets HSD17B13 for nonalcoholic steatohepatitis (NASH).
• SLN360 by Silence Therapeutics targets Lp(a) to address elevated lipoprotein(a), a genetic risk factor for cardiovascular disease.

Emerging Biotech Companies in the siRNA Space

In addition to established players like Alnylam Pharmaceuticals, several emerging biotech firms are making notable contributions:

• Arrowhead Pharmaceuticals is developing a broad pipeline that includes cardiovascular, hepatic, and respiratory targets.
• Silence Therapeutics focuses on precision siRNA delivery using its proprietary mRNAi GOLD™ platform.
• Dicerna Pharmaceuticals, acquired by Novo Nordisk, developed GalXC™ technology for liver-targeted siRNA delivery.
• Sirnaomics is advancing siRNA therapies in oncology and fibrosis, including candidates in topical and injectable formats.
• Aro Biotherapeutics and Nutcracker Therapeutics are exploring novel delivery mechanisms to enhance cell specificity and therapeutic index.

Collaborations and Licensing Deals 

The strategic landscape of siRNA therapeutics is marked by numerous high-value collaborations:

• Sarepta Therapeutics announced a strategic restructuring plan designed to prioritize high-value, high impact programs, meet its 2027 financial obligations, and support its long-term financial viability.
• CRISPR Therapeutics and Sirius Therapeutics announced a strategic partnership to develop and commercialize siRNA therapies.
• AbbVie and ADARx Pharmaceuticals announced a collaboration and license option agreement to develop small interfering RNA (siRNA) therapeutics across multiple disease areas, including neuroscience, immunology and oncology.
• Alnylam has partnered with major pharmaceutical companies including Novartis, Sanofi, Roche, and Regeneron to co-develop and commercialize siRNA-based therapies.
• Arrowhead has ongoing collaborations with Amgen (for ARO-AMG1) and Takeda (for ARO-AAT) in areas like cardiovascular and liver disease.
• Silence Therapeutics entered a licensing agreement with AstraZeneca to develop siRNA drugs for cardiovascular, renal, and metabolic diseases.
• Dicerna had a strategic partnership with Eli Lilly worth over $3 billion before its acquisition by Novo Nordisk.

These partnerships reflect the growing confidence in siRNA as a viable therapeutic platform and serve to accelerate the development, regulatory navigation, and commercialization of RNAi-based drugs. The robust clinical pipeline, coupled with substantial investment and innovation, positions siRNA therapeutics at the forefront of modern medicine.

Challenges and Mitigation Approaches

While siRNA technology provides many advantages over traditional small molecule therapeutics, some challenges need to be addressed, such as delivery efficiency, stability, immune stimulation, and potential off-target effects. Ongoing research and development efforts are focused on overcoming these challenges to harness the full potential of siRNA technology for treating a wide range of diseases. The successful application of siRNA therapeutics in diverse disease conditions can be achieved by addressing these challenges through ongoing research and technological advancements.

siRNA Delivery

The safety and effectiveness of siRNA delivery largely depend on its ability to penetrate and accumulate in the intended tissue or organ. Achieving local delivery enhances the drug’s bioavailability by ensuring that the siRNA reaches its target site efficiently. Over recent decades, a variety of non-viral delivery systems have been explored and are increasingly recognized as promising and reliable approaches for targeted siRNA delivery. However, systemic administration of siRNA presents several challenges, including low bioavailability, rapid clearance from the body, systemic toxicity, and limited ability to specifically target diseased cells or organs. To address these issues, several strategies have been developed, such as employing viral vectors, lipid nanoparticles, chemical modifications, and more recently, tri-GalNAc conjugates. The latter has shown significant promise in achieving targeted delivery of oligonucleotides to hepatocytes, marking a major step forward in oligonucleotide-based therapeutics.

Off-target Effects

Although significant efforts have been made to direct siRNAs to specific targets, research indicates that siRNAs can unintentionally silence non-target genes. Off-target effects may arise due to the innate immune response through post-transcriptional gene suppression; however, siRNA-induced microRNA-like activity is believed to be a primary contributor. To reduce these unintended effects, scientists are focusing on designing siRNA sequences with high specificity for their target genes. One effective approach to minimize off-target interactions involves chemically modifying the nucleotides near the seed region of the siRNA molecule.

Immunogenicity

siRNA molecules have the potential to activate the immune system, as the body often identifies double-stranded RNA (dsRNA), like siRNA, as a marker of viral infection. This recognition can lead to the activation of immune cells, release of inflammatory signals, and production of cytokines. The immunogenic nature of siRNA poses important challenges for therapeutic use. To address this, researchers are employing various strategies to reduce immune activation. One key approach involves introducing structural modifications to the siRNA—such as chemical changes to the sugar backbone or nucleotide bases—to increase stability and decrease immune detection. Additionally, comprehensive screening and optimization are used to select siRNA sequences with minimal immunogenicity. Addressing these immune-related challenges is vital to improving the clinical success of siRNA therapies by enhancing their safety, stability, and overall therapeutic effectiveness.

Manufacturing Challenges of siRNA

The large-scale manufacturing of siRNA-based therapies is often complex and costly. To broaden patient access, it is essential to develop more efficient and economically viable production methods. The overall cost of siRNA manufacturing depends on several factors, including production volume, required purity and quality standards, and any necessary chemical modifications or conjugations. Scaling up synthesis can significantly reduce costs through economies of scale. For instance, siRNA drugs such as patisiran, givosiran, lumasiran, vutrisiran, and nedosiran—used to treat rare genetic disorders—can cost between USD 400,000 and USD 1.64 million per year. Although alternative treatments may have lower direct drug expenses, they often involve highly complex, costly procedures like organ transplants or require long-term specialized care, making siRNA therapies comparatively favorable in terms of overall healthcare burden.

siRNA Market Trends and Future Outlook

The small interfering RNA siRNA therapy market is witnessing robust growth. Key players like Sanofi, Alnylam Pharmaceuticals, Arrowhead, and Dicerna (now part of Novo Nordisk) are leading the way in siRNA analysis, development, and commercialization. Sanofi, in particular, is investing heavily in small interfering RNA (siRNA) technology, positioning itself as a key innovator in RNAi therapy. The siRNA (small interfering RNA) therapeutics market is experiencing rapid expansion and robust investment activity, underpinned by breakthroughs in gene silencing technologies, growing demand for precision medicine, and increasing interest in tackling diseases with limited treatment options. 

Projections suggest the market could surpass all the records by the decade’s end, driven by the rising prevalence of genetic disorders, chronic diseases, and technological advances that enhance siRNA delivery and stability. Notably, improvements in lipid nanoparticle and polymer conjugate platforms have been pivotal in overcoming key delivery barriers, allowing siRNA therapies to reach previously undruggable targets.

The investment landscape for siRNA therapeutics is dynamic and highly active. There has been a surge in mergers and acquisitions (M&A), alliances, and venture capital funding in the sector. Major pharmaceutical companies are acquiring or partnering with innovative biotech startups to strengthen their RNAi (RNA interference) pipelines and leverage next-generation delivery platforms. For instance, in recent months, biopharma leaders like Biogen, AstraZeneca, and GSK have announced strategic collaborations and acquisitions targeting siRNA technology and assets. Venture capital investment is also robust, exemplified by large funding rounds, which aim to accelerate clinical development of siRNA-based therapeutics across disease areas from metabolic disorders to cardiovascular disease.

Geographically, the United States and Europe currently dominate siRNA market revenues, but Asia-Pacific is anticipated to see accelerated growth due to increasing research investment and expanding biotech infrastructure. The innovation ecosystem is further stimulated by regulatory support, favorable reimbursement policies, and competitive activity among pharmaceutical and academic players. Despite the upbeat outlook, the sector continues to grapple with challenges such as targeted delivery complexities, off-target effects, and high development costs, which in turn drive further innovation and strategic investment. With a maturing clinical pipeline, increasing clinical and commercial successes, and a strong M&A and funding environment, the siRNA market is poised for continued transformative growth and high investor interest over the next several years.

Future directions: Combination therapies, personalized medicine

The future direction of siRNA therapeutics in combination therapies and personalized medicine is increasingly demonstrated by current approved drugs and clinical candidates that illustrate these trends. For example, Fitusiran (Qfitlia), approved by the FDA in 2025, targets antithrombin mRNA to rebalance coagulation in patients with hemophilia A or hemophilia B, potentially to be combined with factor replacement therapies or novel hemostatic agents to enhance treatment efficacy and reduce bleeding episodes. This exemplifies combination therapy where siRNA is integrated to modulate disease pathways synergistically with existing treatments. Similarly, Vutrisiran (Amvuttra), approved for hereditary transthyretin-mediated amyloidosis, targets the mutant transthyretin gene, representing a more tailored genetic approach that aligns with precision medicine goals by silencing disease-causing genes specific to patient pathology.

Personalization is evident in siRNA’s ability to target unique genetic drivers: Patisiran (Onpattro), the first FDA-approved siRNA drug for hereditary transthyretin amyloidosis, exemplifies how siRNA therapies address genetically defined diseases by selectively degrading mutant mRNA. Other drugs such as Inclisiran (Leqvio) for hypercholesterolemia use liver-directed GalNAc-siRNA conjugates to precisely reduce PCSK9 expression, potentially allowing dosing regimens tailored by genetic risk or cholesterol levels.

Beyond these, investigational siRNA drugs, like Cemdisiran for complement-mediated diseases and nedosiran for primary hyperoxaluria type 1, demonstrate the expanding pipeline targeting rare conditions with defined molecular bases, creating scope for further personalization. The refinement of delivery systems (e.g., lipid nanoparticles and GalNAc conjugates) enhances tissue specificity, making it feasible to customize siRNA regimens for individual patient profiles.

Combination approaches are also being explored in oncology, where siRNA may be combined with chemotherapy or immunotherapy to overcome resistance or enhance antitumor immune responses. As siRNA platforms mature, the synergy between nucleic acid precision and conventional or novel therapies is expected to accelerate clinical benefits.

In summary, FDA-approved siRNA drugs like patisiran, vutrisiran, inclisiran, and fitusiran illustrate the movement toward combination therapeutic strategies and personalized gene-targeting treatments, supported by advances in delivery technologies and molecular diagnostics that enable effective, patient-specific interventions.

Conclusion

The siRNA (small interfering RNA) therapeutics market is experiencing rapid expansion and robust investment activity, underpinned by breakthroughs in gene silencing technologies, growing demand for precision medicine, and increasing interest in tackling diseases with limited treatment options. In conclusion, siRNA therapeutics represent a transformative advancement in the field of precision medicine, offering an unprecedented ability to silence disease-causing genes with high specificity. With several FDA-approved drugs and a growing clinical pipeline, siRNA has demonstrated its potential across a range of indications—from rare genetic disorders to more prevalent conditions like hypercholesterolemia and certain cancers. Despite this progress, significant challenges remain, particularly in the areas of targeted delivery, stability, and minimizing off-target effects. 

However, continuous innovation in delivery platforms, chemical modifications, and combination strategies is steadily overcoming these barriers. The regulatory environment is also evolving to accommodate the unique nature of RNA-based therapies, paving the way for more streamlined development and approval processes. Looking ahead, the future of siRNA therapeutics is promising, with expanding applications in personalized medicine and potential integration with other cutting-edge modalities such as gene editing and immunotherapy. As scientific understanding deepens and technological solutions mature, siRNA is poised to play a central role in reshaping the therapeutic landscape for a wide array of diseases.

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Frequently Asked Questions

1. What is the function of small interfering siRNA?

The function of small interfering RNA is that it plays a pivotal role in the regulation of gene expression through a highly efficient and specific biological pathway known as RNA interference (RNAi). This mechanism is fundamental for cellular defense, gene regulation, and is increasingly explored for therapeutic applications.

2. What is the primary role of siRNA?

The primary role of small interfering RNA (siRNA) is to mediate gene silencing through a process known as RNA interference (RNAi). siRNAs are double-stranded RNA molecules that specifically target and degrade messenger RNA (mRNA) with complementary sequences, effectively preventing the translation of these mRNAs into proteins. the core function of siRNA is to initiate the degradation of specific mRNA molecules, thereby blocking the synthesis of the corresponding proteins and silencing targeted genes at the post-transcriptional level.

3. What are the benefits of siRNA?

Small interfering RNA (siRNA) offers substantial benefits both as a research tool and a therapeutic agent. Its foremost advantage is its remarkable specificity: siRNAs can be precisely designed to silence any target gene, including mutant alleles that differ from normal genes by as little as a single nucleotide, thus enabling highly targeted therapies for genetic disorders, cancers, and viral infections. siRNAs act exclusively in the cytoplasm without integrating into the genome, which minimizes the risk of permanent genetic changes and unwanted mutations, contributing to a favorable safety profile. Their post-transcriptional mechanism allows for potent and efficient gene silencing, resulting in significant downregulation of disease-causing gene expression even at low doses. Clinically, siRNA-based drugs have demonstrated robust efficacy—for example, significantly lowering cholesterol and triglycerides in dyslipidemia patients and showing therapeutic potential in hard-to-treat diseases. Additionally, siRNAs are cost-effective and adaptable for rapid development against emerging threats or novel targets, while advances in chemical modifications and delivery systems continue to improve their stability and minimize off-target effects, supporting their growing role in precision medicine and drug development.

4. What is the first approved siRNA therapy?

The first approved siRNA therapy is patisiran, marketed as ONPATTRO®. Approved by the US Food and Drug Administration (FDA) in 2018, patisiran is indicated for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy in adults. Developed by Alnylam Pharmaceuticals, this milestone marked the first clinical use of RNA interference (RNAi) as a therapeutic modality, ushering in a new era of gene-silencing medicine. Patisiran works by targeting and degrading mutant transthyretin (TTR) mRNA in the liver, thereby reducing the production of the pathogenic TTR protein responsible for amyloid deposition and neuropathy in hATTR patients.

5. What siRNA drugs are approved by the FDA?

As of 2025, the FDA has approved several siRNA-based drugs, marking significant progress in RNA interference therapeutics. The approved siRNA drugs include:

• Patisiran (ONPATTRO®) – The first FDA-approved siRNA therapy, approved in 2018, used to treat hereditary transthyretin-mediated (hATTR) amyloidosis by targeting mutant transthyretin mRNA.
• Fitusiran (Qfitlia™) – Approved in March 2025, this siRNA drug is used for routine prophylaxis in patients with Hemophilia A or B, with or without inhibitors. It works by reducing antithrombin levels to reduce bleeding episodes.
• Vutrisiran (Amvuttra™) – Another siRNA therapy approved for the treatment of cardiomyopathy associated with wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM).
• Givosiran is a double-stranded small interfering RNA (siRNA) therapeutic designed to reduce the production of toxic heme intermediates in patients with acute hepatic porphyria (AHP), a group of rare genetic disorders affecting heme synthesis in the liver.
• Lumasiran is an siRNA therapeutic that treats primary hyperoxaluria type 1 (PH1), a rare genetic disorder characterized by excessive oxalate production leading to kidney damage.
• Inclisiran is an siRNA drug approved for the treatment of hypercholesterolemia, particularly in patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia.

6. What is gene silencing therapy?

Gene silencing therapy is a medical approach that involves suppressing or “silencing” the expression of specific genes to prevent the production of their associated proteins. This regulation of gene expression occurs through natural cellular mechanisms, primarily RNA interference (RNAi), which utilizes small RNA molecules like small interfering RNA (siRNA) to target and degrade messenger RNA (mRNA) transcripts of the genes. By degrading the mRNA, gene silencing therapy effectively blocks the translation process, thus reducing or eliminating the production of proteins linked to disease processes. Gene silencing therapy holds great therapeutic potential for treating various conditions including genetic disorders, cancers, viral infections, and other diseases by precisely downregulating disease-causing genes without permanently altering the DNA sequence. This makes it a powerful tool for both research and clinical applications, offering targeted and reversible gene regulation.