Glycosylation shapes the efficacy and safety of diverse protein, gene and cell therapies

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Glycosylation, a near-universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation offers an important avenue to developing more efficacious therapies.
In this review, Nathan Lewis’s team discusses specific examples of how variations in glycan structure and glycoengineering impact the stability, safety, and clinical efficacy of protein-based drugs that are already in the market and those still in preclinical development. We also highlight the impact of glycosylation on next-generation biologics such as T cell-based cancer therapy and gene therapy.

Please see the full article in this link!

Lipid-based RNA formulations suitable for therapy

Today's cyclodextrin, , , ,

today’s cyclodextrin:
In this invention, BioNTech SE provides a method of producing a composition comprising RNA lipoplex particles. The main focus of the description is antitumoral therapy.
In the formulation itself, the aqueous colloidal suspension of liposomes is combined with an aqueous solution comprising RNA, thereby producing the composition comprising RNA lipoplex particles. The formulation requires frozen storage conditions; hence the use of cyroprotectant is necessary. The invention proposes mono- di- and oligosaccharides to protect such compositions, including various cyclodextrins and cyclodextrin polymers.
The use of cyclodextrins as cryoprotectants and stabilizers in biopharmaceutical formulations is an emerging technology.

Dr. Hossam Hefesha, Heinrich Haas, Ferdia Bates, Christian Hotz
Katalin Karikó

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Influence of Sugar Modifications on the Nucleoside Conformation and Oligonucleotide Stability: A Critical Review

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Ribofuranose sugar conformation plays an important role in the structure and dynamics of functional nucleic acids such as siRNAs, AONs, aptamers, miRNAs, etc. Several chemical modifications have been introduced into sugar moiety to improve their therapeutic potential over the years. The stability of the oligonucleotide duplexes as well as the formation of stable and functional protein-oligonucleotide complexes are dictated by the conformation and dynamics of the sugar moiety. In this review, Gourav Das Harikrishna and Kiran Gore systematically categorize various ribofuranose sugar modifications employed in DNAs and RNAs so far. We discuss different stereoelectronic effects imparted by different substituents on the sugar ring and how these effects control sugar puckering. Using this data, it would be possible to predict the precise use of chemical modifications and design novel sugar-modified nucleosides for therapeutic oligonucleotides that can improve their physicochemical properties.

See the full article here: Influence of Sugar Modifications on the Nucleoside Conformation and Oligonucleotide Stability: A Critical Review

Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability

drug delivery

today’s cyclodextrin:
is about developing antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPβCD) was used as a stabilizer and an electrospinning matrix from one of the best pharma groups in Hungary (FirePharma Research Group BME – Budapest University of Technology and Economics) collaborating with Janssen Inc.

The fibrous HPβCD–antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPβCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning, such as scale-up and downstream processing of the fibers.

Edit Hirsch, Márió Nacsa, Edina Szabó, Panna Vass, Julia Domjan, Attila Farkas,Zsuzsanna Eke, Tamás Vigh, Sune Klint Andersen, Geert Verreck, György Marosi and Zsombor Kristof Nagy et al

See the full article here: Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability


Chemistry, structure and function of approved oligonucleotide therapeutics

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Chemistry, structure and function of approved #oligonucleotide therapeutics by Martin Egli (Vanderbilt University) and Muthiah (Mano) Manoharan (Alnylam Pharmaceuticals).
Eighteen nucleic acid therapeutics have been approved for the treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. 
Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2′-fluoro-RNA, 2′-O-methyl RNA, and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2′-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability, and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.

See the full article here: Chemistry, structure and function of approved oligonucleotide therapeutics

Controlled drug delivery mediated by cyclodextrin-based supramolecular self-assembled carriers: From design to clinical performances

Today's cyclodextrin,

today’s #cyclodextrin:
achieving controlled release with cyclodextrins can be really challenging, yet it is doable. In fact, there are multiple strategies to get there. In this review, Jana Ghitman and Voicu Stefan Ioan collected different approaches of cyclodextrins-based drug delivery forms that are suitable for co-delivery systems, non-viral vectors for gene delivery, and theranostics.
This review presents the latest achievements in nanoparticle-based supramolecular architectures, taking into account the main synthesis methods and the stimuli that control the release (light-responsive, pH-responsive, redox-responsive, and multi-responsive). The review also presents applications and also the present status regarding commercial systems based on cyclodextrins and their characteristics.

See the full article here:

Controlled drug delivery mediated by cyclodextrin-based supramolecular self-assembled carriers: From design to clinical performances


Cyclodextrin-Based Nanoparticles for Delivery of Antisense Oligonucleotides Targeting Huntingtin

drug delivery, ,

Check out the most recent paper of our collaborators in the GENEGUT Horizon Europe consortia presenting cyclodextrin-based nanoparticles for delivery of antisense oligonucleotides targeting huntingtin. Even if we were not part of this story, we are proud to get involved in the next chapter!

University College Cork – Monique Culturato Padilha Mendonça, PhD, Caitriona O’Driscoll et al
APC Microbiome Ireland – John Cryan

See the full article here

Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs

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As fellow stakeholders in developing novel drug delivery in gene therapy, we greatly admire the review of Sean Dilliard and Daniel Siegwart from The University of Texas Southwestern Medical School describing passive, active and endogenous organ-targeted lipid and polymer nanoparticles. Amazing compilation!

See the full article here

Two papers on the uses of hyper-branched CD-polymer:

Today's cyclodextrin, , , , ,

Fresh from the oven of the Francesco Trotta and Adrián Matencio Durán (Università degli Studi di Torino) lab, two papers on the uses of hyper-branched CD-polymer:
No 1: use as an anticoagulant, which is a very innovative application for CDs that are getting more and more spotlight

See the full article here

No 2: use as transfection promoters of plasmids.

See the full article here.

I congratulate you on this ambitious research goal, loved both papers and look forward to seeing from sprouting from the collaboration you recently started with CarboHyde!
Yousef Khazaei monfared, Mohammad Mahmoudian, Claudio Cecone, Fabrizio Caldera, Sanya Haiaty, Reza Rahbarghazi, Parvin Zakeri-Milani, Gjylije Hoti, Fabrizio Caldera, Roberta Cavalli

A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells

drug delivery, ,

After reporting on intracellular protein delivery yesterday, today we share the latest news on RNA delivery to prostate cancer cells using cyclodextrin nanoparticles.
Universidad de Castilla-La Mancha, Instituto de Salud Carlos III, Universidad de Sevilla (Jose Manuel Garcia Fernandez, Valentin Ceña et al)

See the full article here