bims-meglyc 2023-12-31 papers

Issue of 2023‒12‒31
four papers selected by
Silvia Radenkovic

Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231219272

The Rare Diseases Clinical Research Network: a model for clinical trial readiness.

Background: The current road to developing treatments for rare diseases is often slow, expensive, and riddled with risk. Change is needed to improve the process, both in how we think about rare disease treatment development and the infrastructure we build to support ongoing science. The National Institutes of Health (NIH)-supported Rare Diseases Clinical Research Network (RDCRN) was established to advance the diagnosis, management, and treatment of rare diseases and to promote highly collaborative, multi-site, patient-centric, translational, and clinical research. The current iteration of the RDCRN intends to build upon and enhance successful approaches within the network while identifying innovative methods to fill gaps and address needs in the approach to the rare disease treatment development process through innovation, collaboration, and clinical trial readiness.Objective: The objective of this paper is to provide an overview of the productivity and influence of the RDCRN since it was first established 20 years ago.
Design and methods: Using a suite of tools available to NIH staff that provides access to a comprehensive, curated, extensively linked data set of global grants, patents, publications, clinical trials, and FDA-approved drugs, a series of queries were executed that conducted bibliometric, co-author, and co-occurrence analysis.
Results: The results demonstrate that the entire RDCRN consortia and network has been highly productive since its inception. They have produced 2763 high-quality publications that have been cited more than 100,000 times, expanded international networks, and contributed scientifically to eight FDA-approved treatments for rare diseases.
Conclusion: The RDCRN program has successfully addressed some significant challenges while developing treatments for rare diseases. However, looking to the future and being agile in facing new challenges that arise as science progresses is important.

Keywords: clinical trial readiness; consortium; network; rare diseases; translational research

DOI: https://doi.org/10.1177/26330040231219272

Tissue Eng Part B Rev. 2023 Dec 27.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes: From Regulatory Status to Clinical Translation.

Catarina Soares, Maria Ribeiro.

Cardiovascular diseases, considered the deadliest worldwide by the World Health Organization (WHO), lack effective therapies for regenerating cardiomyocytes. With their self-renewal and pluripotency capabilities, stem cell therapies are increasingly used in precision medicine. Induced pluripotent stem cells (iPSCs) are a promising alternative to embryonic stem cells. However, Good Manufacturing Practice (GMP) principles are not yet adapted for large-scale production of iPSCs. Additionally, the quality risk for iPSC products may not always be possible to eliminate, potentially jeopardizing the health of patients. This review aims to identify critical quality attributes (CQAs) for iPSC-derived cardiomyocyte cardiomyocytes for the development of cardiovascular therapy to ensure compliance with regulations and safety for patients. . Moreover, this work includes the identification of CQAs that must be considered in the development of this cellular therapy. To attain these goals the literature review was conducted with articles related to iPSCs and iPSC-derived cardiomyocyte therapies, legislation and regulatory guidances guidelines of the EMA (European Medicines Agency), FDA (Food and Drug Administration), and PMDA (Pharmaceuticals and Medical Devices Agency). As In conclusion, additional regulations and guidelines are needed to monitor differentiation, maturation, and tumorigenicity. GMP-compliant cell banks and fast-track approval systems may increase accessibility for patients.

DOI: https://doi.org/10.1089/ten.TEB.2023.0080

Nucleosides Nucleotides Nucleic Acids. 2023 Dec 28. 1-12

Zebrafish as a model for study of disorders in pyrimidine nucleotide metabolism.

Liya Wang.

Pyrimidine nucleotides are not only the building blocks of DNA and RNA but also participate in multiple cellular metabolic processes, including protein, lipid and polysaccharide biosynthesis. Pyrimidine nucleotides are synthesized by two distinct pathways-the de novo and salvage pathways. Disorders in pyrimidine nucleotide metabolism cause severe neurodegenerative disorders in human. For example, deficiency in thymidylate kinase, an essential enzyme in dTTP synthesis, causes severe microcephaly in human patients. Zebrafish mutants selected by insertion mutagenesis that results in inactive enzymes in pyrimidine metabolism showed also neurological and developmental disorders. In this work I have summarized current data on neurological and developmental disorders caused by defects in enzymes in pyrimidine nucleotide metabolism in zebrafish and compared to human. All these data suggest that zebrafish is a useful animal model to study pathogenic mechanism of neurological disorders due to defect in pyrimidine nucleotide metabolism.

Keywords: Zebrafish; animal model; enzyme defect; neurological and developmental disorders; pyrimidine nucleotide metabolism

DOI: https://doi.org/10.1080/15257770.2023.2298742

Basic Res Cardiol. 2023 Dec 26.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Qiuyu Sun, Cory S Wagg, Berna Güven, Kaleigh Wei, Amanda A de Oliveira, Heidi Silver, Liyan Zhang, Ander Vergara, Brandon Chen, Nathan Wong, Faqi Wang, Jason R B Dyck, Gavin Y Oudit, Gary D Lopaschuk.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

Keywords: Cardiac energy metabolism; Cardiac glucose oxidation; Glucose oxidation; Heart failure; Pyruvate dehydrogenase; Pyruvate dehydrogenase kinase

DOI: https://doi.org/10.1007/s00395-023-01020-2