RNA Interference Drug Research Articles

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma.

ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly. Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia. ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.

Transcutaneous Immunotherapy for RNAi: A Cascade-Responsive Decomposable Nanocomplex Based on Polyphenol-Mediated Framework Nucleic Acid in Psoriasis.

Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.

RNA interference: from target validation to therapeutics

Generally, a new targeted medicine takes a long time, usually 5 to 15 years, from the discovery and validation of its target to its actual use in treating a disease. There is no doubt that steps such as target validation and target evaluation are essential in preclinical development of new drugs to ensure safety, bioavailability, and efficacy of the drug, and in the target validation phase, RNA interference (RNAi) is a very important method. RNAi drug has double-stranded RNA function, so the targeted mRNA of a specific gene sequence is degraded, its transcription process is abnormal, which leads to gene silencing, and related protein synthesis failure. RNAi technology could specifically shut off specific genes, and, it is a targeted drug with great potential. Therefore, RNAi technology can be used to treat some rare diseases, such as acute hepatic porphyria (AHP) in adults, by using drugs as carriers. In 1998, Andrew Fire and Craig C. Mello first defined the RNAi phenomenon and was honored with the Nobel Prize in Physiology or Medicine in 2006 for their discovery of RNAi and their outstanding contributions to the field of gene silencing. Since then, RNAi drugs have been studied by pharmaceutical scientists around the world, but many of the previous drugs have been stopped at the evaluation stage due to their chemical instability. Until October 2018, the worlds first RNAi drug (patisiran) was successfully marketed so that the RNAi drug development became popular again because of remarkable pesticide effect.

Amide Modifications in the Seed Region of the Guide Strand Improve the On-Target Specificity of Short Interfering RNA.

RNA interference (RNAi) is a well-established research tool and is also maturing as a novel therapeutic approach. For the latter, microRNA-like off-target activity of short interfering RNAs (siRNAs) remains as one of the main problems limiting RNAi drug development. In this communication, we report that replacement of a single internucleoside phosphodiester in the seed region (nucleotides 2 to 7) of the guide strand with an amide linkage suppressed the undesired microRNA-like off-target activity by at least an order of magnitude. For the specific siRNA targeting the PIK3CB gene, an amide modification between the third and fourth nucleotides of the guide strand showed the strongest enhancement of specificity (completely eliminated off-target silencing) while maintaining high on-target activity. These results are important because off-target activity is one of the main remaining roadblocks for RNA based drug development.

RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies.

RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biologic activity away from their natural equivalents. Novel technologies in development today seek to use intact cells to yield true biologic RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiologic and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA-approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran) as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biologic RNAi agents for research and development. SIGNIFICANCE STATEMENT: In our review, we summarize the major concepts of RNA interference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of US Food and Drug Administration-approved RNAi medications and those siRNAs and miRNA-based therapeutics that entered the clinical investigations. Novel approaches to producing new true biological RNAi molecules for research and development are highlighted.

FC010: Multicentric Experience with RNA Interference Medication (OXLUMO®) in Patients with Primary Hyperoxaluria Type 1

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of the glyoxylate metabolism in the liver inducing severe endogenous oxalate overproduction. Massive hyperoxaluria leads to recurrent urolithiasis and/or nephrocalcinosis and often early end-stage kidney failure. Current treatment options were scarce until the first RNA interference drug, Oxlumo® (Lumasiran, Alnylam Pharmaceuticals, USA) can now be prescribed. Oxlumo® targets the mRNA of glycolate oxidase and, thus, prevents its translation. This reduces production of glyoxylate (i.e. the precursor to oxalate) and thus oxalate production. However, glycolate production increases. METHOD We herein report our current clinical experience with s.c. administration of Oxlumo adhering to provide dosage recommendation. A total of 25 PH1 patients were included. Seven patients were on haemodialysis, 1 patient on peritoneal dialysis and 17 were on stable kidney function at start of Oxlumo medication (eGFR > 30 and <55 mL/min in 2 patients and >70 mL/min in all others). The male: female ratio was 15:10, and the age range was 1–62 years of age at start of treatment. In both groups plasma oxalate (Pox) and glycolate (Pglyc) were determined before the first and every next Oxlumo dosage. In non-dialysis patients, urinary oxalate (Uox) and urinary glycolate in 24 h urines were analysed at same interval plus monthly collection until month 6 of treatment and thereafter in 6 weeks’ intervals, if Uox did not reach near normalisation, or had increased again at end of dosing interval (3 monthly). Oxalate and glycolate were determined using ion chromatography/mass spectrometry in the same lab. RESULTS We now report data of those patients, who have received at least four dosages of Oxlumo (n = 15). Non-dialysis patients: Uox was normal (<0.5 mmol/1.73 m2/d) in two patients, in five patients it was near normal (1.5 times the upper limit, <0.75) and in three patients Uox was above 0.75 mmol/1.73 m2/d. Pox was normal in seven and above 7.4 µmol/L in three patients. In seven patients data were available at fifth to seventh dosage interval. Here, one patient had a normal Uox; in all other patients Uox was above 0.75 mmol/1.73 m2/d before next dosage. In the seven dialysis patients median Pox did not really decline over time (median of 45.1 at baseline, n = 7; and 39.9 post fourth dosage, n = 5), as was median Pglyc (86.05/71.1). Patient-specific follow-up differed and must also be related to co-medication with B6. For example, one dialysis patient remained stable with Pglyc below 2 µmol/L (under B6) and another patient experienced Pglyc > 1 mmol/L (without B6). CONCLUSION Oxlumo® has reduced Uox in 7/10 patients after the fourth dosage. However, adjustment of dosage intervals or dosage per se are necessary in the majority of patients to reach the goal of treatment, e.g. at least near normalisation of urinary oxalate excretion. In dialysis patients lack of reduction of Pox maybe because patients dissolve systemic oxalate deposits. However, specific imaging (bone MRI) in three of the dialysis patients did not show improvement of oxalate osteopathy over 6 and 9 months, respectively.

Running interference: lumasiran and other RNA interference therapeutics for kidney diseases

RNA interference (RNAi) is a biological process that directly modulates gene activity. RNAi-based therapeutic agents, which bind specifically to target messenger RNA (mRNA) sequences, allow downstream silencing of the respective target protein. In recent years, RNAi-based agents have become a major novel tool for the treatment of several rare diseases. In 2018, the first RNAi drug approved by the FDA in the United States was patisiran for hereditary transthyretin (TTR) amyloidosis, followed by the approval of givosiran for acute hepatic porphyria, and lumasiran for primary hyperoxaluria.

The Struggling Odyssey of Infantile Primary Hyperoxaluria.

Introduction: Oxalate overproduction in Primary Hyperoxaluria type I (PH1) leads to progressive renal failure and systemic oxalate deposition. In severe infantile forms of PH1 (IPH1), end-stage renal disease (ESRD) occurs in the first years of life. Usually, the management of these infantile forms is challenging and consists in an intensive dialysis regimen followed by a liver-kidney transplantation (combined or sequential).Methods: Medical records of all infants with IPH1 reaching ESRD within the first year of life, diagnosed and followed between 2005 and 2018 in two pediatric nephrology departments in Brussels and Paris, have been reviewed.Results: Seven patients were included. They reached ESRD at a median age of 3.5 (2–7) months. Dialysis was started at a median age of 4 (2–10 months). Peritoneal dialysis (PD) was the initial treatment for 6 patients and hemodialysis (HD) for one patient. Liver transplantation (LT) was performed in all patients and kidney transplantation (KT) in six of them. A sequential strategy has been chosen in 5 patients, a combined in one. The kidney transplanted as part of the combined strategy was lost. Median age at LT and KT was 25 (10–41) months and 32.5 (26–75) months, respectively. No death occurred in the series. At the end of a median follow-up of 3 years, mean eGFR was 64 ± 29 ml/min/1.73 m2. All patients presented retinal and bone lesions and five patients presented bones fractures.Conclusion: Despite encouraging survival figures, the morbidity in IPH1 patients remains extremely heavy and its management presents a huge challenge. Thanks to the newly developed RNA-interference drug, the future holds brighter prospects.

Insight Into the Prospects for RNAi Therapy of Cancer.

RNA interference (RNAi), also known as gene silencing, is a biological process that prevents gene expression in certain diseases such as cancer. It can be used to improve the accuracy, efficiency, and stability of treatments, particularly genetic therapies. However, challenges such as delivery of oligonucleotide drug to less accessible parts of the body and the high incidence of toxic side effects are encountered. It is therefore imperative to improve their delivery to target sites and reduce their harmful effects on noncancerous cells to harness their full potential. In this study, the role of RNAi in the treatment of COVID-19, the novel coronavirus disease plaguing many countries, has been discussed. This review aims to ascertain the mechanism and application of RNAi and explore the current challenges of RNAi therapy by identifying some of the cancer delivery systems and providing drug information for their improvement. It is worth mentioning that delivery systems such as lipid-based delivery systems and exosomes have revolutionized RNAi therapy by reducing their immunogenicity and improving their cellular affinity. A deeper understanding of the mechanism and challenges associated with RNAi in cancer therapy can provide new insights into RNAi drug development.

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic–pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1–4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.

RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia

Abstract Background Elevated LDL-C and triglyceride rich lipoproteins (TRLs) are independent risk factors for cardiovascular disease (CVD). Genetic deficiency of angiopoietin-like protein 3 (ANGPTL3) is associated with reduced circulating levels of LDL-C, triglycerides (TGs), VLDL-C, HDL-C and reduced CVD risk, with no described adverse phenotype. ARO-ANG3 is a RNA interference drug designed to silence expression of ANGPTL3. Single doses of ARO-ANG3 have been shown to reduce ANGPTL3, TGs, VLDL-C and LDL-C in healthy volunteers (HVs, AHA 2019). We report the effects of multiple doses of ARO-ANG3 in HVs with a focus on the duration of action. Methods ARO-ANG3 was administered subcutaneously to HVs on days 1 and 29 at doses of 100, 200 or 300 mg (n=4 per group). Measured parameters included ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C. Follow up is ongoing. Results All HVs have received both doses and follow-up is currently through week 16 (12 weeks after second dose). Mean nadir for ANGPTL3 levels occurred 2 weeks after the second dose (−83–93%) with minimal change for 200 and 300 mg but 16% recovery for 100 mg at week 16. Mean TGs and VLDL-C reached nadir earlier (3 wks, −61–65%) without apparent dose response and minimal change for any dose at wk 16. LDL-C nadir occurred 4–6 wks after the second dose (−45–54%), again with minimal evidence for dose response or change through wk 16. HDL-C was reduced 14–37% at wk 16. ARO-ANG3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events have been headache and upper respiratory infections. Conclusions Genetic deficiency of ANGPTL3 is a cause of familial combined hypolipemia and is associated with a decreased risk of CVD. Using RNAi to selectively suppress ANGPTL3 production reproduces these genetic effects with a duration of at least 12 weeks following a second dose and with good tolerability over 16 wks. ANGPTL3 inhibition results in lowering of LDL-C and TRLs which may confer protection against CVD in patients with atherogenic mixed dyslipidemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals

To Conjugate or to Package? A Look at Targeted siRNA Delivery Through Folate Receptors.

RNA interference (RNAi) applications have evolved from experimental tools to study gene function to the development of a novel class of gene-silencing therapeutics. Despite decades of research, it was not until August 2018 that the US FDA approved the first-ever RNAi drug, marking a new era for RNAi therapeutics. Although there are many limitations associated with the inherent structure of RNA, delivery to target cells and tissues remains the most challenging. RNAs are unable to diffuse across cellular membranes due to their large size and polyanionic backbone and, therefore, require a delivery vector. RNAi molecules can be conjugated to a targeting ligand or packaged into a delivery vehicle. Alnylam has used both strategies in their FDA-approved formulations to achieve efficient delivery to the liver. To harness the full potential of RNAi therapeutics, however, we must be able to target additional cells and tissues. One promising target is the folate receptor α, which is overexpressed in a variety of tumors despite having limited expression and distribution in normal tissues. Folate can be conjugated directly to the RNAi molecule or used to functionalize delivery vehicles. In this review, we compare both delivery strategies and discuss the current state of research in the area of folate-mediated delivery of RNAi molecules.

Chemical Approaches for RNAi Drug Development

RNA interference (RNAi) is the standard method of suppressing gene expression because of its target specificity, potency, and ability to silence the expression of virtually any gene. Using 21-mer small interfering RNA (siRNA) is the general approach for inducing RNAi, as siRNA can be easily prepared using a DNA/RNA synthesizer. Synthetic siRNA can be chemically modified to increase the potency of RNAi activity and abrogate innate immune stimulation. However, designing chemically modified siRNA requires substantial experimentation. A practical method for understanding the interaction of siRNA and RNAi-related proteins and how modifications affect RNA-protein interactions is therefore needed. Plasmid DNA (pDNA) expressing short hairpin RNA (shRNA) can also be used to induce RNAi. pDNA produces numerous shRNAs that induce RNAi with potent and longterm RNAi activity, even if only one pDNA molecule is delivered to the nucleus. However, this approach has some drawbacks with regard to its therapeutic application, such as a low pDNA transfection efficiency due to its huge molecular size and innate immune responses induced by extra genes, such as CpG motifs. To overcome these issues with RNAi inducers (siRNA and pDNA), our group developed some chemical approaches using chemically modified oligonucleotides. This article focuses on our two original approaches. The first involves the groove modification of siRNA duplexes to understand siRNA-protein interactions using 7-bromo-7-deazaadenosine and 3-bromo-3-deazaadenosine as chemical probes, while the second involves the generation of RNAi medicine using chemically modified DNA, known as an intelligent shRNA expression device (iRed).

RNAi drugs: Next generation drugs?

Gene therapy aims to apply biotechnological techniques to correct a defective gene through administrating therapeutic nucleic acids or editing a defective gene. The approaches used in gene therapy include traditional transgene, genome editing, such as CRISPR/CAS9, RNA interference (RNAi) and antisense oligonucleotides (ASOs), etc. Gene therapy is promising as a main approach of disease treatment in the future. Particularly, RNAi is a potential rising-star in this field. RNAi is a biological phenomenon in which small RNA molecules inhibit gene expression at post-transcriptional level. There are two categories of RNA molecules, which include small interfering RNAs (siRNAs) and microRNAs (miRNAs). Both RNA types can induce gene silencing through distinct mechanisms, such as degrading mRNA, decreasing mRNA stability, or preventing protein translation. The major difference between siRNAs and miRNAs is that siRNAs are double stranded RNAs with completely paired sequences and high specificity for its targeted mRNA, whereas miRNAs are single stranded RNAs with incomplete complementary sequences and multiple targets on mRNAs. When compared with traditional therapeutic drugs which target defective proteins, siRNA and miRNA drugs offer advantages, such as higher specificity, lower toxicity, and easy manipulation of the defective genes of interest, etc. ASOs technique is another approach to silence a gene at the post-transcriptional level by several mechanisms including recruiting RNase H to cleave and degrade the targeted mRNA, alternative splicing, blocking translation, or binding to miRNA to regulate gene expression. The first-ever RNAi drug was approved in the United States and Europe in 2018, a significant milestone in pharma-cology which represents an era of a new type of drug. This event has been nominated as one of the top ten 2018 scientific breakthroughs. Apparently, it is expected that several other RNAi drugs will be approved for marketing in the near future. The first siRNA drug was used on a rare genetic disease that only affected about 50000 people worldwide. The major obstacle to widely-spread use RNAi drugs is the low delivery efficiency of small RNA molecules into cells or tissues. Various approaches have been developed for RNAi drug delivery in vivo including nanoparticles, cationic lipids, viruses, and polymers. However, they all have limitations for therapeutic applications. The first ASO drug was approved in 1998. Several other ASO drugs were approved in the following twenty years. However, the ASOs drugs have not become a mainstream drug yet due to some limitations other than delivery vehicle, such as adverse side effects from both on-target and off-target toxicities. The RNAi drugs and ASOs drugs may face similar problems in wide clinical applications. The approval of the first RNAi drug will greatly pave a way for the development of more RNAi drugs. We expect current technical hurdles in RNAi delivery will be resolved in the near future and RNAi drugs will become mainstream as next generation drugs.

Roche to pay big for HBV RNAi therapy

Roche will pay $200 million to license Dicerna Pharmaceuticals’ RNA interference (RNAi) drug candidate for hepatitis B virus (HBV). Dicerna could also earn up to $1.5 billion in future payments for the molecule, which is in a Phase I clinical trial. The program will complement Roche’s experimental small-molecule and antisense oligonucleotide HBV treatments. Other companies developing RNAi therapies for HBV include Johnson & Johnson and Vir Biotechnology.

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran.

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class thatresults in the effect firstdescribed by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present withmutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing processinvolves the binding of siRNA guide strand to 3'-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC)asthe first biochemical drug effect. Patisiran 0.3mg/kg is administered intravenously every 3weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study.At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15±2.14μg/mL and 184±159μg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18months. Additionally,the modified body mass index showed positive outcomes. Altogether, the data across phase I-III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

The challenge of delivering RNA-interference therapeutics to their target cells.

Delivery difficulties brought the nascent research field to its knees, but approval of the first RNA interference drug offers hope. Delivery difficulties brought the nascent research field to its knees, but approval of the first RNA interference drug offers hope.

Investigational RNAi Therapeutic Targeting C5 Is Efficacious in Pre-clinical Models of Myasthenia Gravis

Complement-mediated damage to the neuromuscular junction (NMJ) is a key mechanism of pathology in myasthenia gravis (MG), and therapeutics inhibiting complement have shown evidence of efficacy in the treatment of MG. In this study, we describe the development of a subcutaneously administered N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C5 component of complement that silences C5 expression in the liver (ALN-CC5). Treatment of wild-type rodents with ALN-CC5 resulted in robust and durable suppression of liver C5 expression. Dose-dependent serum C5 suppression was observed in non-human primates, with a lowering of serum C5 of up to 97.5% and the concomitant inhibition of serum complement activity. C5 silencing was efficacious in ameliorating disease symptoms in two standard rat models of MG, demonstrating the key role of circulating C5 in pathology at the NMJ. Improvement in disease activity scores and NMJ pathology was observed at intermediate levels of complement activity inhibition, suggesting that complete ablation of complement activity may not be required for efficacy in MG. The pre-clinical studies of ALN-CC5 and efficacy of C5 silencing in rat models of MG support further clinical development of ALN-CC5 as a potential therapeutic for the treatment of MG and other complement-mediated disorders.

Alnylam and Regeneron sign big RNAi deal

Alnylam Pharmaceuticals, the first company to bring an RNA interference (RNAi) drug to market, has struck an $800 million–plus deal with Regeneron Pharmaceuticals to develop RNAi therapies for eye ...

Is this the decade of RNA?

RNA should be a terrible drug target. Its long, noodle-like structure (shown) lacks the nooks and crannies that small-molecule drugs use to grab onto proteins and thereby control them. But a decades-old disregard for RNA is starting to change. In August 2018, the US Food and Drug Administration approved the first-ever RNA interference drug, which uses a double-stranded RNA molecule to prevent the production of disease-related proteins. In the past two years, several start-ups have launched to show that some RNAs can, just like proteins, be drugged with small molecules. And a group of companies recently emerged with plans to drug proteins that make modifications to RNA, part of the budding field of epitranscriptomics. In this episode of Stereo Chemistry, C&EN visits Alnylam Pharmaceuticals, Novartis, and Accent Therapeutics to discuss these three strategies and to understand how RNA-modulating therapies will compete in the wider world of drug discovery. Listen now