Cell & Gene Therapy Bioprocessing & Commercialization is the most focused event for cost effective and efficient cell, gene and immunotherapy approaches. CGT delivers the focused science and business content designed specifically for the cell therapy and regenerative medicine fields, while providing a pivotal gathering place for connecting industry, funding sources, government and academia. Welcome to visit us at SINOPEG's Booth#104at CGT, Boston Convention and Exhibition Center, USA from 27th to 30th September. https://informaconnect.com/cell-therapy-bioprocessing/ #event #CGT #Boston SINOPEG is a dynamic science company with professional R&D, Manufacturing and Sales capability. The company is mainly engaged in drug delivery system (DDS) and new medical materials business. Founded in 2011, SINOPEG has a team of highly qualified and science background employee personnel. We devote ourselves to research, develop and produce high quality Polyethylene glycol, Polyethylene glycol derivatives, Block copolymers, Anti-diabetic drug side chains, lipids for LNPs, GalNAc conjugates, ADC and ProTAC Linker, etc. Please contact us at sales@sinopeg.com 

#ASOs #antisense oligonucleotide #GalNAc #drug delivery #ligand targeting   Drug development scheme using the GalNAc conjugate, is better suited for selecting BNA-based ASOs, especially for the treatment of liver-associated diseases.   gnitude   https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(22)00428-2   Antisense oligonucleotides (ASOs) containing bridged nucleic acids (BNAs) have been proven to be very powerful. However, there is still a challenge to ensure a reliable discovery and translational development scheme for this class of ASOs with wider therapeutic windows. The robustness of the scheme was demonstrated in the context of the selection of ASOs, which have two different BNA chemistries (2,′4′-BNA/locked nucleic acid [LNA] and amido-bridged nucleic acid [AmNA]) targeting human proprotein convertase subtilisin/kexin type 9 (PCSK9). A two-step process was shemed, including a unique and sensitive in vitro screening approach, called Ca2+ enrichment of medium (CEM) transfection, and a ligand-targeted drug delivery approach to better reach target tissues, averting unintended accumulation of ASOs. An N-acetylgalactosamine (GalNAc) ligand then was appended to the candidate ASO to further broaden the therapeutic margin by altering the molecule’s pharmacokinetics. With reduced nephrotoxicity in rats, the GalNAc conjugate, HsPCSK9-1811-LNA, was found to be at least ten times more potent in non-human primates. Overall, a drug development scheme was shown better suited for selecting clinically relevant BNA-based ASOs, especially for the treatment of liver-associated diseases.

Bagsværd, Denmark , 2 2 August 2022 – Novo Nordisk today announced headline results from a phase 2 clinical trial with CagriSema, a once-weekly subcutaneous combination of semaglutide and a novel amylin analogue, cagrilintide. The trial investigated the efficacy and safety of a fixed dose combination of CagriSema (2.4 mg semaglutide and 2.4 mg cagrilintide) compared to the individual components semaglutide 2.4 mg and cagrilintide 2.4 mg, all administered once weekly, in 92 people with type 2 diabetes and overweight. People were equally randomised among the three treatment arms. In the trial, the mean baseline HbA1c was 8.4% and the mean baseline body weight was 106 kg. After 32 weeks of treatment, people treated with CagriSema achieved a numerically higher HbA1c reduction of 2.18%-points compared to a reduction of 1.79%-points for people treated with semaglutide and 0.93%-points with cagrilintide alone. People treated with CagriSema achieved a numerically higher body weight reduction of 15.6% compared to a reduction of 5.1% for people treated with semaglutide and 8.1% with cagrilintide alone1. In the trial, CagriSema appeared to have a safe and well-tolerated profile. “We are encouraged by the impressive phase 2 results for CagriSema in people with type 2 diabetes,” said Martin Holst Lange, executive vice president for Development at Novo Nordisk. “The results indicate that CagriSema reduces blood sugar more than semaglutide alone and the weight loss seen in the trial confirms the substantial weight lowering potential of CagriSema”. Based on the results, Novo Nordisk is now planning to initiate a phase 3 development programme for CagriSema in people with type 2 diabetes in 2023. The CagriSema (2.4 mg semaglutide and 2.4 mg cagrilintide) phase 3 programme in people with overweight and obesity, REDEFINE, is expected to begin in the fourth quarter of 2022. Source:  https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=131155

Nearly half of all vaccines go to waste due to the strict temperature regulation needed throughout the manufacturing process and vaccine administration, meaning they need to be refrigerated to remain effective. To mitigate this, researchers from ETH Zurich (Germany) in collaboration with Nanoly Bioscience (CO, USA) have developed a new hydrogel to package vaccines and increase their thermal stability.   The hydrogel is based on a biocompatible synthetic polymer, polyethylene glycol (PEG), that acts like a molecular Tupperware, keeping large complex molecules separated from each other, like the proteins found in vaccines, antibodies and gene therapies.   In vaccines, the PEG-based hydrogel encapsulates proteins enabling them to withstand a higher range of temperature fluctuations by preventing them from aggregating together. Without the packaging, cold chain vaccines tend to withstand a temperature range of 2°C – 8°C (35°F – 45°F). With this reversible packaging system, the temperature range is increased to 25°C – 65°C (75°F – 150°F).   The hydrogel capitalizes on dynamic covalent bonds, creating a reversible platform that can easily release the proteins from their Tupperware box by adding a simple sugar solution. This means vaccines can be easily recovered at their point of use.     The PEG-based hydrogel could yield economic benefits by reducing the costs and health risks that are associated with cold supply chains and mean more funding can be put towards the production of vaccines.     Before this molecular Tupperware can be rolled out, safety studies and clinical trials are needed. Until then, the technology could be used in a variety of ways including transporting heat-sensitive enzymes used in cancer research or protein molecules in research lab settings.     Source:https://www.biotechniques.com/bioengineering-biophysics/increasing-vaccine-thermal-stability-with-peg-based-hydrogels/

– Patisiran Met the Primary Endpoint with a Statistically Significant Improvement in 6-Minute Walk Test Compared to Placebo at 12 Months – – Patisiran Also Met the First Secondary Endpoint with a Statistically Significant Improvement in Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire, Compared to Placebo at 12 Months – – Patisiran Demonstrated Encouraging Safety and Tolerability Profile in Patients with ATTR Amyloidosis with Cardiomyopathy – – Company Plans to File a Supplemental New Drug Application in U.S. in Late 2022 – – Full Data Will Be Presented at the 18th International Symposium on Amyloidosis – – Alnylam to Host Conference Call Today at 8:00 am ET – August 03, 2022 07:00 AM Eastern Daylight Time CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, met the primary endpoint of change from baseline in the 6-Minute Walk Test (6-MWT) at 12 months compared to placebo (p-value 0.0162). The study also met the first secondary endpoint of change from baseline in quality of life compared to placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) (p-value 0.0397). “We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis” Tweet this The study also included additional secondary composite outcome endpoints to be tested in a hierarchical manner. A non-significant result (p-value 0.0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo. As a result, formal statistical testing was not performed on the final two composite endpoints, which were not powered for statistical significance given the short duration of the study — all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (nominal p-value 0.9888), and in the overall population (nominal p-value 0.5609). Patisiran also demonstrated an encouraging safety and tolerability profile, with deaths numerically favoring the patisiran arm. “We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. Thes...

mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables effificient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-ofexperiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specifific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentifified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profifile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarififies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNALNP-based antitumor immunotherapy. INTRODUCTION Messenger RNA (mRNA) vaccines are extremely versatile, as mRNA sequences can be easily tailored to encode any antigen of interest, enabling both rapid and mass-scale vaccine development against emerging pathogens as well as personalized vaccine design against cancers. Key to the success of the currently approved SARS-CoV2 mRNA vaccines and of many mRNA-based prophylactic vaccines in clinical development are lipid-based nanoparticles (LNPs), delivery vehicles that mediate effificient mRNA expression in situ and endow the vaccine with intrinsic adjuvant properties.  LNPs are composed of an ionizable lipid, a phospholipid, cholesterol, and a PEGylated lipid, with the ionizable lipid being considered the most important driver of mRNA expression. In contrast to their predecessors having a cationic charge across a wide variety of pH ranges, ionizable lipids are pH-sensitive lipids that endow the LNPs with a positive, membrane fusion-promoting charge at endosomal pH while having a neutral charge at physiological pH. The ionizable lipid is required to encapsulate the mRNA and drives endosomal escape. The PEGylated lipid improves LNP stability and controls the interaction of the LNPs with blood proteins and cells. Cholesterol and the phospholipid contribute to LNP stability and endosomal membrane destabilization. Intramuscular or subcutaneous administration of mRNA LNPs has been reported to elicit CD8 T cell responses against the mRNA encoded antigen. In t...

Few dispute that the rapid development and approval of two mRNA vaccines against COVID-19 was an unmitigated success, or that the evolving field of gene therapy has delivered multiple successful treatments for a range of rare diseases. Still, genomic medicines is a field that’s ripe for further innovation, in areas ranging from the development of improved delivery vehicles to the streamlining of manufacturing.   Three areas of genomic medicines could benefit greatly from an integrated approach to development: gene editing, gene therapy and mRNA medicines. All of these modalities hold great potential in the development of innovative therapies to treat cancer, autoimmune disease, rare inherited diseases and more. Engaging partners early in the development process is critical to assembling cutting-edge tools to enable efficient end-to-end development and manufacturing.   Customizing gene editing for improved efficiency CRISPR gene editing is being developed as a treatment for a range of applications, including CAR-T cells for cancer, gene-edited stem cells to treat diabetes and ex-vivo gene editing to treat the blood disorder beta thalassemia.   Integrated DNA Technologies (IDT)* can customize guide RNAs for common CRISPR research applications, as well as emerging gene-editing approaches like prime editing and research using the Cas13 enzyme. IDT also offers the Alt-R™ CRISPR-Cas9 System with the HiFi CRISPR-Cas9 nuclease, allowing for more precise gene editing with less of the off-target activity that can be a concern in gene editing.   Aldevron offers additional research-grade and GMP versions (SpyFiTM Cas9 Nuclease), which can help accelerate experimental therapies. Aldevron has partnered with external partners as well and can offer a full library of novel CRISPR nucleases to qualified customers, such as Eureca-V™ Nuclease, the wild-type MAD7™ CRISPR Type-V nuclease from Inscripta.   Improving the delivery of gene therapy Lipid nanoparticles (LNPs) are widely used to deliver mRNA, CRISPR components and other nucleic acids into cells, but developing the LNP chemistry and process is challenging. Precision NanoSystems (PNI) has advanced technologies that can ease the process of developing and manufacturing LNPs. Its GenVoy Delivery Platform includes a novel lipid library and LNP reagents optimized for key applications including vaccines, gene editing and cell therapies. And researchers can use PNI’s desktop NanoAssemblr® platform with NxGen™ microfluidics to make well-formed, stable LNPs using a production process that is scalable from small batch discovery research to GMP production.   The viral vectors used to deliver gene and cell therapies are also in high demand, intensifying the need for technologies that can ease development and manufacturing. Aldevron offers a range of plasmids essential for the development of viral vectors. And with the help of some key partnerships, Danaher’s life sciences compan...

Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and rapid waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized trimers (S-2P) of the wildtype spike, which have shown a reduced neutralizing activity against the variants of concern B.1.617.2 and B.1.1.529. Recently, a new version of spike trimer, termed VFLIP (five (V) prolines, Flexibly-Linked, Inter-Protomer disulfide) was developed. Based on the original amino acid sequence of the wildtype spike, VFLIP was genetically engineered by using five proline substitutions, a flexible cleavage site amino acid linker, and an interprotomer disulfide bond. It has been suggested to possess native-like glycosylation, and greater pre-fusion trimeric stability as opposed to S-2P. Here, we report that the spike protein VFLIP-X, containing six rationally substituted amino acids to reflect emerging variants (K417N, L452R, T478K, E484K, N501Y and D614G), offers a promising candidate for a next-generation SARS-CoV-2 vaccine. Mice immunized by a circular mRNA (circRNA) vaccine prototype producing VFLIP-X had detectable neutralizing antibody titers for up to 7 weeks post-boost against SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). In addition, a balance in TH1 and TH2 responses was achieved by immunization with VFLIP-X. The researchers's results indicate that the VFLIP-X delivered by circRNA induces humoral and cellular immune responses, as well as broad neutralizing activity against SARSCoV-2 variants. The study used the following products from SINOPEG: ionizable lipidoid SM-102 (Sinopeg), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Sinopeg), cholesterol (Sinopeg), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000, Sinopeg) A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera, Antiviral Research, Volume 204, 2022, 105370, ISSN 0166-3542, https://doi.org/10.1016/j.antiviral.2022.105370. (https://www.sciencedirect.com/science/article/pii/S0166354222001395)