Hongene Biotech Corporation

As the calendar winds down on another fruitful year, we are thrilled to close the chapter with remarkable research: 𝗔𝗻 𝗜𝗺𝗽𝗿𝗼𝘃𝗲𝗱 𝗣(𝗩) 𝗧𝗵𝗶𝗼-𝗢𝗹𝗶𝗴𝗼𝗻𝘂𝗰𝗹𝗲𝗼𝘁𝗶𝗱𝗲 𝗦𝘆𝗻𝘁𝗵𝗲𝘀𝗶𝘀 𝗣𝗹𝗮𝘁𝗳𝗼𝗿𝗺🎉! This research presents an improved synthetic platform capable of synthesizing therapeutic oligonucleotides with greater stereocontrol and at a lower cost, marking an important advancement in drug development and chemical synthesis fields. The researchers focused on three key improvements to the P(V) oligonucleotide platform: 1️⃣𝗥𝗲𝗮𝗴𝗲𝗻𝘁 𝗗𝗲𝘃𝗲𝗹𝗼𝗽𝗺𝗲𝗻𝘁: They introduced a more affordable phosphorus-sulfur incorporation reagent, 4-bromothiophenol (Ψᴮʳ), as an alternative to the expensive Pentafluorothiophenol. 2️⃣𝗟𝗶𝗻𝗸𝗲𝗿 𝗦𝘆𝘀𝘁𝗲𝗺: They developed a robust linker system to improve stability during the synthesis process. 3️⃣𝗣𝗿𝗼𝘁𝗲𝗰𝘁𝗶𝗻𝗴 𝗚𝗿𝗼𝘂𝗽𝘀 𝗦𝘁𝘂𝗱𝘆: They conducted a systematic study of nucleobase protecting groups to simplify the synthesis process. ✅𝗠𝗮𝗶𝗻 𝗥𝗲𝘀𝘂𝗹𝘁𝘀: ✔ 𝗖𝗼𝘀𝘁 𝗥𝗲𝗱𝘂𝗰𝘁𝗶𝗼𝗻: The new reagent, Ψᴮʳ, was found to be competent in preparing nucleoside monomers and reduced the cost of the leaving group by 10-fold. ✔ 𝗟𝗶𝗻𝗸𝗲𝗿 𝗦𝘁𝗮𝗯𝗶𝗹𝗶𝘁𝘆: A Sar-Glu-based linker was identified as the most stable under P(V) coupling conditions, showing a 94% recovery after 120 coupling cycles. ✔ 𝗣𝗿𝗼𝘁𝗲𝗰𝘁𝗶𝗻𝗴 𝗚𝗿𝗼𝘂𝗽 𝗖𝗼𝗺𝗽𝗮𝘁𝗶𝗯𝗶𝗹𝗶𝘁𝘆: The study found that certain protecting groups, such as Pya, dma, and nonprotected bases, were compatible with SPOS, while Benzoyl groups were not. They also identified suitable protecting groups for each base, allowing for the synthesis of a full-length, mixed-base oligonucleotide with similar yield and quality to those made with previously published monomers. These improvements not only streamline the adoption of the P(V)-platform for therapeutic oligonucleotide synthesis but also make it more accessible for industrial and academic applications. The optimized reagents, linkers, and protecting groups contribute to a more efficient and cost-effective synthesis process, potentially accelerating the discovery and development of new therapeutic oligonucleotides！ Congratulations to all contributors🎉! Molhm Nassir Luca Gherardi Scripps Research Richard Redman Elsie Biotechnologies Our Hongene team is proud to be part of this remarkable work 👏 ! David Butler Feng Yao Yang Yang #oligonucleotide #RNAtherapeutics #SPOS

In the ever-evolving landscape of drug discovery, two methodologies have emerged as groundbreaking tools for researchers: Click Chemistry and Bioorthogonal Chemistry. These approaches not only revolutionized how we connect molecules but also opened new avenues for exploring complex biological systems and developing novel therapeutic agents. Click Chemistry was pioneered by Nobel laureate K. Barry Sharpless and refers to a class of fast and reliable chemical reactions that are modular, wide in scope, give very high yields, and generate only inoffensive byproducts. The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most popular click reactions, celebrated for its efficiency and versatility. It enables the assembly of molecular building blocks with extraordinary precision, making it an invaluable tool for medicinal chemistry. This led to the development of bioorthogonal chemistry, which introduced reactions like the strain-promoted azide-alkyne cycloaddition (SPAAC) and the inverse electron demand Diels-Alder (iEDDA) reaction. These reactions are not only fast and efficient but also compatible with living cells, making them invaluable tools in biological research. In the realm of drug development, click and bioorthogonal chemistry have opened new horizons. DNA-encoded libraries (DELs) have been a game-changer, allowing for the rapid screening of vast numbers of compounds to identify potential drug candidates. By attaching a unique DNA barcode to each molecule, researchers can efficiently sort through millions of compounds to find those that bind specifically to a target protein. This approach has significantly accelerated the lead compound discovery process. Moreover, these techniques have facilitated the synthesis of complex molecules like antisense oligonucleotides and protein-drug conjugates. Antisense oligonucleotides can selectively modulate gene expression, offering a promising avenue for treating genetic diseases. Protein-drug conjugates, on the other hand, have transformed cancer therapy by enabling targeted drug delivery to cancer cells, thereby increasing efficacy and reducing side effects. As we look ahead, the potential applications of click and bioorthogonal chemistry continue to expand. Their role in personalized medicine is particularly exciting, as they can be tailored to target specific genetic mutations or disease pathways. Additionally, ongoing research is exploring new click reactions and bioorthogonal strategies to further enhance their utility in living systems. Explore more about applications of click and bioorthogonal chemistry within medicinal chemistry in this latest review article: https://lnkd.in/ePqrQ5Ng #ClickChemistry #BioorthogonalChemistry #DrugDevelopment #ASO #DrugDiscovery #MedicinalChemistry #PersonalizedMedicine

A wrap for 2024 ——A comprehensive list of FDA Drug Approvals 2024! As of now, in 2024, the Center for Drug Evaluation and Research (CDER) of the U.S. FDA has approved a total of 50 new drugs, including 34 new molecular entities (NMEs) and 16 biologics. Among the NMEs, small molecules are the majority, accounting for approximately 91% (31 drugs), with the remainder including nucleic acids and peptide drugs; among the biologics, 81% are antibody-based (10 monoclonal antibodies, 3 bispecific antibodies), with the rest being fusion proteins and Type A botulinum toxin. Overall, the number of new drugs approved by CDER in 2024 is not much different from that of 2023, and the number of "first-in-class" (FIC) drugs is also roughly the same. In 2023, CDER approved 20 FIC drugs, which accounted for 36% of the total number of new drugs approved. In 2024, CDER approved 22 FIC drugs, representing 44% of the new drugs approved. Among these FIC drugs, small molecules almost account for half (10 drugs), while antibody drugs are another main force of innovation (5 monoclonal antibodies, 3 bispecific antibodies). As for the therapeutic areas, oncology (28%) remains the field with the highest number of new drugs approved by CDER in 2024, followed by rare diseases (20%), and then, in order, cardiovascular and metabolic diseases, infectious diseases, autoimmune diseases, dermatological diseases, and mental and neurological diseases. The approval of these new drugs brings new hope for treatment to patients and demonstrates the vigorous development and relentless pursuit of the pharmaceutical industry. Looking forward, we hope that more new drugs will pass stringent scientific review and be safely and effectively applied in clinical practice, providing more and better treatment options for patients worldwide! #drugapproval #healthcare #smallmolecues #biologics #pharmaceuticals

#Breakthrough Engineers from the University of Pennsylvania have modified lipid nanoparticles (LNPs) to not only cross the blood-brain barrier (BBB) but also to target specific types of cells. This marks a significant step toward potential next-generation treatments for neurological diseases, like Alzheimer’s and Parkinson’s! Delivering nucleic acid therapeutics to the brain remains a significant challenge due to the BBB, which prevents approximately 98% of small molecule drugs and 100% of large molecule drugs. Although LNPs have become the most advanced nucleic acid delivery vehicles in clinical use, achieving tissue-specific delivery has proven difficult. To address this, a team led by Michael J Mitchell designed a platform of peptide-functionalized lipid nanoparticles (pLNPs) for the systemic delivery of mRNA to the brain. They utilized click chemistry to functionalize LNPs with peptides (RVG29, T7, AP2, and mApoE) that target receptors overexpressed on brain endothelial cells and neurons. ✅Key Research Findings ✔Peptide Targeting Improves Transfection Efficiency: In vitro experiments showed that specific peptide-functionalized LNPs significantly improved the mRNA transfection efficiency of brain endothelial cells and neuronal cells. ✔Enhanced Blood-Brain Barrier Endocytosis and Neuronal Transfection: Transwell model experiments demonstrated that pLNPs can cross the endothelial monolayer and improve the transfection of basal lateral neuronal cells. ✔In Vivo mRNA Transfection: In a mouse model, all pLNPs improved brain transfection efficiency compared to non-targeted LNPs, with RVG29 and AP2 showing approximately a 70-fold increase. ✔Neuronal Transfection: Flow cytometry analysis indicated that RVG29 LNPs significantly increased the percentage of mCherry-positive neurons, demonstrating significant improvements in neuronal transfection. This research highlights the potential of pLNPs as a platform for delivering mRNA therapeutics across the BBB to treat various neurological diseases. This work not only provides new strategies for the treatment of neurological diseases but also marks significant progress in mRNA drug delivery technology! Congratulations to all contributors!🎉 Emily Han Sophia Tang Image credit the paper: https://lnkd.in/eYtjzNbg #LNPs #lipidnanoparticles #mRNA #drugdelivery #RNAtherapeutics #neurology #genetransfer

#breakingnews The FDA approved Ionis Pharma's TRYNGOLZA (olezarsen) as the first-ever treatment for adults living with familial chylomicronemia syndrome (#FCS) as an adjunct to diet! FCS is a rare, genetic form of severe hypertriglyceridemia (sHTG) that can lead to potentially life-threatening acute pancreatitis (AP). Symptoms of FCS may appear in infancy, but some patients do not develop symptoms until adulthood. The estimated incidence of the disease is 1 to 10 cases per million people. TRYNGOLZA is the first-ever FDA-approved ASO therapy that significantly and substantially reduces triglyceride levels in adults with FCS and provides a clinically meaningful reduction in AP events when used with an appropriate diet (≤20 grams of fat per day). TRYNGOLZA is self-administered via an auto-injector once monthly. The FDA approval was based on positive data from the Phase 3 Balance clinical trial. In the Balance stud: ✅ TRYNGOLZA 80mg demonstrated a statistically significant placebo-adjusted mean reduction in triglyceride levels of 42.5% from baseline to six months. Reductions from baseline to 12 months were further improved, with TRYNGOLZA achieving a placebo-adjusted 57% mean reduction in triglycerides. ✅ A substantial, clinically meaningful reduction in AP events over 12 months; one patient (5%) experienced one episode of AP in the TRYNGOLZA group compared with seven patients (30%) who experienced 11 total episodes of AP in the placebo group. ✅A favorable safety profile. The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and at a >3% higher frequency than placebo) were injection site reactions (19% and 9%, respectively), decreased platelet count (12% and 4%, respectively) and arthralgia (9% and 0%, respectively). #ASO #GalNac #RNAtherapeutics #drugdelivery #geneticdisorder #familialchylomicronemiasyndrome

Warmest wishes for a joyous Holiday season from Hongene team🎄 🎊 🎇!   May your days be filled with laughter, love, and cherished moments with loved ones. We are grateful for the opportunity to connect with you this year and extend our sincere appreciation for your continued support🤗!   Wishing you a prosperous and fulfilling New Year 🎉!

A recent article provides a comprehensive analysis of patent compounds in LNP formulations for siRNA, offering valuable insights for researchers and developers in making informed technological and commercial decisions! The researchers mined 2,994 patents, 265 formulas, 7,674 compounds, and 28,789 fragments to sketch the empirical golden ratio of lipid materials in LNP formulation, disclose advanced technology in the formulation, characterize high-frequency fragments of heads, linkers, and tails in both novel cationic lipids as well as targeting lipids, and establish a virtual focus library of LNP materials. 💡 Key findings include: ✔️𝗣𝗮𝘁𝗲𝗻𝘁 𝗧𝗿𝗲𝗻𝗱 𝗔𝗻𝗮𝗹𝘆𝘀𝗶𝘀 The study identifies a steady increase in LNP-related patent applications, indicating growing investment in intellectual property within the field. ✔️𝗟𝗡𝗣 𝗙𝗼𝗿𝗺𝘂𝗹𝗮𝘁𝗶𝗼𝗻 𝗥𝗮𝘁𝗶𝗼𝘀 It highlights the changes in the mole ratios of lipid components in LNP formulations over two distinct periods, noting a concentration around the median for cationic lipids, helper lipids, and steroids from 2011 to 2021. ✔️ 𝗣𝗿𝗲𝘃𝗮𝗹𝗲𝗻𝗰𝗲 𝗼𝗳 𝗖𝗮𝘁𝗶𝗼𝗻𝗶𝗰 𝗟𝗶𝗽𝗶𝗱𝘀 Among novel lipids, cationic lipids account for the majority, and the study also provides a comprehensive analysis of targeting lipids. ✔️𝗦𝘁𝗿𝘂𝗰𝘁𝘂𝗿𝗮𝗹 𝗗𝗶𝘃𝗲𝗿𝘀𝗶𝘁𝘆 𝗼𝗳 𝗟𝗶𝗽𝗶𝗱𝘀 The analysis points out the structural diversity in the head groups, linkers, and tails of cationic lipids, which significantly influences the performance of LNPs. ✔️𝗧𝗮𝗿𝗴𝗲𝘁𝗶𝗻𝗴 𝗟𝗶𝗽𝗶𝗱𝘀 𝗜𝗻𝘀𝗶𝗴𝗵𝘁𝘀 The study provides insights into targeting lipids, revealing various targeting ligands and structural features that could enhance the specificity of LNP delivery. By comprehensively analyzing patent compounds in LNPs, the article reveals the technological trends and chemical structural characteristics in this field, guiding future research directions and commercial applications, and holds significant scientific and commercial value! Kudos to all contributors! Image credit: https://lnkd.in/eEU9rM7n #siRNA #LNP #lipidnanoparticles #RNAtherapetics #drugdelivery

#Breakthrough Engineers from the University of Pennsylvania have developed a lipid nanoparticle (LNP) that delivers mRNA therapeutic to the placenta to treat life-threatening pregnancy disorders! Pre-eclampsia is one of the leading causes of stillbirths and prematurity worldwide, and it occurs in 3 to 5% of pregnancies. Current treatments focus on managing symptoms rather than addressing root causes and often promote preterm delivery as the only definitive cure. With no drug available to slow disease progression, engineering LNPs for extrahepatic mRNA delivery to the placenta is an attractive therapeutic option for pre-eclampsia. In this recent article, researchers from Michael Mitchell's lab utilized advanced LNP technology to deliver VEGF mRNA to the placenta, targeting the underlying dysfunction in pre-eclampsia. The researchers screened 98 LNP formulations using high-throughput barcoding to identify a placenta-specific candidate, LNP 55. LNP 55 was encapsulated with VEGF mRNA and tested in two mouse models of pre-eclampsia. A single intravenous injection was administered, and the biodistribution of LNP 55 was assessed using luminescence and fluorescence imaging. The study monitored maternal blood pressure, fetal health outcomes, immune modulation, and placental vascularization. Results showed that LNP 55 efficiently delivered VEGF mRNA to the placenta, significantly reducing pre-eclampsia symptoms in the mouse models. Treated mice showed restored maternal blood pressure, improved fetal outcomes, and reduced levels of the antiangiogenic marker sFlt-1, indicating increased VEGF availability. The therapy also improved systemic immune responses by reducing inflammatory cytokines. This marks a significant advancement in targeted RNA-based therapeutics and provides a foundation for future clinical research to combat pre-eclampsia and enhance maternal-fetal health！ Congratulations to all contributors!🎉 Find out more: https://lnkd.in/eyE-yPjv #RNAtherapeutics #mRNA #LNP #lipidnanoparticles #preeclampsia #drugdelivery #bioengineering

In a recent discussion, we explored the potential of chemoenzymatic ligation for synthesizing oligonucleotides like siRNA and sgRNA from short oligonucleotide fragments. As global demand for siRNA APIs is projected to surge in the coming decade—particularly in the cardiovascular disease space—ligation technology offers a promising pathway for achieving the large-scale production needed to support this expanding market. The current method for manufacturing oligonucleotide fragments utilizes a well-established four-step solid-phase oligonucleotide synthesis (SPOS) cycle, supported by flow synthesizers like the OligoProcess™. However, this approach presents several significant challenges, outlined below: 👉 𝗦𝗰𝗮𝗹𝗮𝗯𝗶𝗹𝗶𝘁𝘆 Current SPOS methods that utilize flow synthesizers are limited to batch sizes of approximately 10 kg. While adequate for rare disease, scaling up to produce tons of oligonucleotide fragments to manufacture APIs for common diseases would require production of hundreds of batches—a time-intensive and resource-heavy scaling-out approach. 👉 𝗖𝗼𝘀𝘁 Manufacture with SPOS relies on large volumes of expensive raw materials, specialized equipment, complex purification, and lengthy processing in GMP suites, all factors that contribute to the high cost of production and the final price paid by customers. 👉 𝗘𝗻𝘃𝗶𝗿𝗼𝗻𝗺𝗲𝗻𝘁𝗮𝗹 𝗦𝘂𝘀𝘁𝗮𝗶𝗻𝗮𝗯𝗶𝗹𝗶𝘁𝘆 The SPOS process is resource-intensive, typically consuming several tons of raw materials to produce a single kilogram of oligonucleotide. As future manufacturing scales increase, the environmental impact of this approach is a concern for long-term sustainability. 💡  𝗪𝗵𝗮𝘁’𝘀 𝗻𝗲𝘅𝘁? Promising innovations are under development to address these challenges and enable scalable, cost-effective, and sustainable oligonucleotide fragment manufacturing. Stay tuned for insights into these solutions. In the meantime, don’t miss our on-demand video featuring Chief Technology Officer David Butler! https://lnkd.in/e52VcKWd ✔️ Check our recent discussions: 1. Oligonucleotide Synthesis Technology https://lnkd.in/eNRM7j54 2. Mechanism and properties of ligation reaction https://lnkd.in/ezMx6gKj 3. Robust methods of oligonucleotide ligation application https://lnkd.in/eiNe5RMi 4. Advantageous features of ligation technology for oligonucleotide CMC https://lnkd.in/e6q62hUZ #oligonucleotides #RNA #siRNA #sgRNA #RNAtherapeutics #geneediting #oligonucleotidesynthesis #ligationtechnology

#Excitingnews A recent study presents a new drug candidate, a PrP-lowering divalent siRNA, to treat prion disease! Prion diseases are fatal, incurable neurodegenerative disorders caused by the misfolding of prion protein (PrP).  Chronic reduction of PrP levels delays disease in animals, and genetic proofs of concept indicate that aggressive brain-wide suppression of PrP expression, even transiently, has the potential to halt the disease and allow complete clearance of prions from the brain. 50% lowering of PrP increases both survival time and healthy life in prion-infected mice but does not prevent symptom onset nor halt disease progression. Additional drug candidates should seek to reduce PrP expression to even lower levels. Recently described divalent si-RNAs (di-siRNAs), a powerful new RNA-targeting technology capable of reducing levels of specific disease-causing proteins by >99% across the brain, offers the first opportunity to suppress PrP to levels that may offer full protection from disease and to test the potential for a one time cure, offering a new path forward against prion disease and perhaps many other brain diseases. In this preprint, scientists from Broad Institute of MIT and Harvard and UMass Chan Medical School identified a highly potent siRNA sequence against the human PrP gene and determined that a chemical scaffold incorporating extended nucleic acid and a 3′ antisense tail unmatched to the RNA target yields superior potency. The study showed that the new drug candidate, 2439-s4, was highly potent, with the ability to reduce PrP expression to as little as 17% of the original levels in whole brain hemispheres after a single dose. The drug candidate showed activity up to 6 months post-dose and characterized the effect of repeat dosing on target engagement. The research confirmed that a fixed tail and a reduced phosphorothioate AS strand with extended nucleic acid (exNA) linkages improved potency. The findings suggest that divalent siRNA 2439-s4 could be a promising new therapeutic approach for treating prion diseases. Congratulations to all contributors for this incredible work🎉 ! Check the preprint: https://lnkd.in/d_Ud6pYC Prion Alliance: https://lnkd.in/dwhuqcuK #priondisease #prions #neurodegeneration #siRNA #drugdevelopment #drugmodality #RNAtherapeutics