Use of Artificial Intelligence in Drug Development: WACKER, CordenPharma, LMU, and HU Berlin Train Machine Learning Algorithm for the Formulation of RNA Actives

As an active member of an international team developing ways to deliver oligonucleotides (GENEGUT) we cheer for novel approaches in this field.
Now, WACKERCorden Pharma – A Full-Service CDMO, Ludwig-Maximilian University, and Humboldt University use AI in drug development: they train machine learning algorithms for the formulation of RNA actives.
The aim is to develop a new generation of lipid nanoparticles (LNPs), which are a key component of RNA-based pharmaceuticals. Based on these formulations, a machine learning algorithm is to be trained that automatically identifies the best constituents for new RNA formulations – as yet a particularly time-consuming and costly development stage. The three-year project will start on April 1, 2023, and is receiving funding of some €1.4 million from the German Federal Ministry for Economic Affairs and Energy.

See the full press release here

Novoxyne and CarboHyde explore together cyclodextrin-based methods to reprogram somatic cells

Dr. Atsou Ochi recently published his invention related to methods for reprogramming somatic cells into pluripotent stem cell-like cells. Such cells may express pluripotency-inducing genes, including Oct4, Nanog, and Sox2, without introducing exogenous genes, proteins, or chemicals. The discovery that the inhibition of mechanosensitive and stretch-activated ion channels in somatic cells specifically activates pluripotency-inducing factor genes inspired the cell reprogramming culture methods in which somatic cells were incubated with the inhibitor, GsMTX4, against mechanosensitive and stretch-activated ion channels, cultured on the soft hydrogel surface, or treated with cholesterol depletion substance, methyl-beta-cyclodextrin (MβCD). 

Described methods produce pluripotent stem cell-like cells and subsequently re-differentiated cells, which include adipocytes, osteocytes, and neuronal cells. Methods may be combined to increase the efficiency of somatic cell reprogramming. 

To take the next step in development, Novoxyne and CarboHyde started a multiple-staged collaboration project to assess the effects of various cyclodextrins as reprogramming agents of somatic cells, components of stem cell differentiation, and future tools in stem cell-based therapies. 

Novoxyne and Dr Ochi will focus on comparing the effects of different cyclodextrin derivatives on cell redifferentiation, while CarboHyde’s expertise will be used to select and customize this project’s best-working cyclodextrin derivatives.

“We have always had a deep interest in using carbohydrates in novel ways of biotechnology. In fact, two out of our in-house pipeline programs are developed in these directions. Our collaboration with Novoxyne is likely to become a strong third one in a field that holds both great promise and huge challenges in the future of pharmaceutics. I am sure that this collaboration will be mutually rewarding and may open novel insights in the application of cyclodextrins in biotechnology” said CarboHyde’s CEO József Tóth about this upcoming collaboration.

ABOUT CARBOHYDE

CarboHyde is a private preclinical pharmaceutical start-up specializing in developing carbohydrate-based APIs. Our team consists of a small group of seasoned scientists with over 50 years of cumulative experience in the field of carbohydrate chemistry, analysis and pharmaceutical development. The company’s core focus is neurodegenerative diseases, yet we also have other pre-clinical programs in various unmet medical indications. Fully embracing the pharmaceutical development ecosystem, we utilize contract research organizations (CRO) and other companies focusing on CMC and clinical development to make our drug development process efficient. CarboHyde’s management team has extensive experience in medicinal chemistry, marketing, and pharmaceutical development. In addition, CarboHyde is supported by experienced advisers, consultants, and carbohydrate veterans.

ABOUT NOVOXYNE Novoxyne is a research company founded by Atsuo Ochi dedicated to discovering cures to human diseases. We have developed therapeutic fusion proteins based on the checkpoint receptor ligands and cytokines. We have also developed a groundbreaking reprogramming technology that converts somatic cells to stem cells without gene transfection. Our reprogramming technology quickly makes the limitless number of stem cells from any somatic cells and stem cell therapy will become very accessible and safe. No gene transfection, no embryonic stem cell, and no purification of mesenchymal stem cell is necessary for our technology to prepare a large number of stem cells.

Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin

Peroxisomal disorders (PDs) are a heterogeneous group of diseases caused by defects in peroxisome biogenesis or functions. X-linked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene, which encodes a transporter mediating the uptake of very long-chain #fattyacids (VLCFAs). The curative approaches for PDs are very limited. Researchers from Wuhan University investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs – by individually knocking down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulations in the lysosome. 2-Hydroxypropyl-β-#cyclodextrin (HPCD) effectively alleviated the #cholesterol accumulation phenotype in PD-mimicking cells by reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes. In ABCD1 knockdown cells, HPCD treatment lowered reactive oxygen species and VLCFA to normal levels. In Abcd1 knockout mice, HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex. The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration. These results suggest that defective cholesterol transport underlies most, if not all, PDs, and that HPCD or potentially other CDs can serve as a novel and effective strategy for the treatment of PDs.

see the full article here: Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin

Use of cyclodextrin to enhance solubility of substrates and increase enzymatic glycosylation reaction efficiency

We are particularly fond of biotech applications of #cyclodextrin, and the invention of DoubleRainbow Biosciences gives a simple solution for exploiting their potential in this field and helps understand how CDs could be used to improve enzymatic glycosylation efficiency.
Yasmin ChauJacob Wirth, DING, Sheng, Jing-Ke Weng

See the full patent on Patentscope: Use of cyclodextrin to enhance solubility of substrates and increase enzymatic glycosylation reaction efficiency

Wrestling with Lipinski’s rule of 5

Wrestling with Lipinski’s rule of 5
The chemist introduced the guidelines more than 25 years ago. Drug designers still disagree about their value.
Even Lipinski counts himself among those that don’t think the rule of 5 should be hard and fast. “I am still slightly taken aback by how some people want strict guidelines without consideration of nuance,” says the chemist, who retired from Pfizer in 2002 and is now a consultant. “At heart, I am an experimentalist, and I believe that generally, experimentation trumps calculation. So one should try hard to measure the properties of an interesting compound even if the calculations on that compound may not look too promising.”

See more about Lipinski’s rule of 5 here

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

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

FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors

today’s #cyclodextrin:
using CDs as non-viral gene delivery systems is a more or less known and upcoming application. Yet using them in adenoviral vector-based gene therapy is certainly something novel.
ADSTILADRIN (Ferring Pharmaceuticals) is a non-replicating adenoviral vector-based gene therapy approved by the FDA in December 2022 for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. It was developed for intravesical instillation.
ADSTILADRIN is a sterile, clear to opalescent suspension, and contains no preservative. The combined use of polysorbate 80 and HPBCD in an adenovirus composition is already precedented in Jcovden (previously COVID-19 Vaccine Janssen) vaccine, wherein the function of cyclodextrin is disclosed as cryoprotectant. Since ADSTILADRIN is shipped frozen at ≤ -60°C, the use of HPBCD due to its cyroprotectant effect is also justified herein.
The second indication of ADSTILADRIN is currently under clinical trial (phase III) in the USA for Malignant pleural mesothelioma, a rare, aggressive cancer of the pleural surface associated with asbestos exposure per patent application US 2020/0164091. 

See the FDA’s article here: FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors

A chitin oligosaccharide vaccine for preventing fungal infection and a preparation method

A chitin oligosaccharide vaccine for preventing fungal infection is formed by coupling a mixture of chitin oligosaccharides and a carrier protein. The provided vaccine developed by Shandong First Medical University(Shandong Academy Of Medical Sciences)is highly immunogenic, is able to activate Th17 cell immunity, and may identify and protect from infection caused by fungi.

See the full patent on Espacenet: A chitin oligosaccharide vaccine for preventing fungal infection and a preparation method


Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

today’s cyclodextrin:
This review by Thorsteinn LoftssonHakon Hrafn Sigurdsson, and Phatsawee Jansook pulls a brave topic. It accounts some of the unexpected results the authors have encountered during their studies of CDs as pharmaceutical excipients.
CDs are constantly surprising investigators with their unique physicochemical properties. CDs are solubilizing complexing agents of poorly soluble drugs in aqueous solutions, while they can also act as organic cosolvents like ethanol. CDs and their complexes self-assemble in aqueous solutions to form both nano- and microparticles. The nanoparticles have diameters that are well below the wavelength of visible light; thus, the solutions appear to be clear. However, the nanoparticles can result in erroneous conclusions and misinterpretations of experimental results. CDs can act as penetration enhancers, increasing drug permeation through lipophilic membranes, but they do so without affecting the membrane barrier.

See the full article here: Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions