bims-meglyc 2023-04-02 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–04–02
29 papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

The Association of the Polymorphisms in the FUT8-Related Locus with the Plasma Glycosylation in Post-Traumatic Stress Disorder.
Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation.
The Impact of Artificial Intelligence in the Odyssey of Rare Diseases.
Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration.
Charcot-Marie-Tooth neuropathies: Current gene therapy advances and the route toward translation.
Glycophagy mediated glucose-induced changes of hepatic glycogen metabolism via OGT1-AKT1-FOXO1Ser238 pathway.
Orphan Drugs in Neurology-A Narrative Review.
In Vitro Maturation of Human Pluripotent Stem Cell-Derived Myotubes.
Enhancing Equitable Access to Rare Disease Diagnosis and Treatment around the World: A Review of Evidence, Policies, and Challenges.
Ketones and the Heart: Metabolic Principles and Therapeutic Implications.
Pathogenic Variants Associated with Rare Monogenic Diseases Established in Ancient Neanderthal and Denisovan Genome-Wide Data.
Genetic Testing in Patients With Congenital Heart Disease: You Do No Harm When Using the Right Tools!
Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.
Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges.
Mitochondrial transplantation as a promising therapy for mitochondrial diseases.
Gene Modification Therapies for Hereditary Diseases in the Fetus.
Stem cell-based modeling and single-cell multiomics reveal gene-regulatory mechanisms underlying human skeletal development.
Liver organoids: established tools for disease modeling and drug development.
Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives.
Regulation of Adenine Nucleotide Metabolism by Adenylate Kinase Isozymes: Physiological Roles and Diseases.
Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry.
A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male.
Gene therapy for inborn errors of immunity: Base editing comes into play.
Single-cell and spatially resolved transcriptomics for liver biology.
Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration.
Cellular reprogramming of fibroblasts in heart regeneration.
Direct cardiac reprogramming: A new technology for cardiac repair.
Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm.
The importance of pseudouridylation: human disorders related to the fifth nucleoside.

Int J Mol Sci. 2023 Mar 16. pii: 5706. [Epub ahead of print]24(6):

The Association of the Polymorphisms in the FUT8-Related Locus with the Plasma Glycosylation in Post-Traumatic Stress Disorder.

Lucija Tudor, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Marcela Konjevod, Suzana Uzun, Oliver Kozumplik, Ninoslav Mimica, Gordan Lauc, Dubravka Svob Strac, Nela Pivac.

  The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the FUT8 gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with FUT8-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and FUT8-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of FUT8-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD.

Keywords:  FUT8-related polymorphisms; N-glycans; fucosyltransferase 8 (FUT8); glycosylation; haplotype; plasma; post-traumatic stress disorder

DOI:  https://doi.org/10.3390/ijms24065706
Int J Mol Sci. 2023 Mar 07. pii: 5109. [Epub ahead of print]24(6):

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation.

Ana Marín-Quílez, Lorena Díaz-Ajenjo, Christian A Di Buduo, Ana Zamora-Cánovas, María Luisa Lozano, Rocío Benito, José Ramón González-Porras, Alessandra Balduini, José Rivera, José María Bastida.

  Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.

Keywords:  glycosylation; inherited platelet disorder; inherited thrombocytopenia; platelet clearance; syndromic manifestation; thrombopoiesis

DOI:  https://doi.org/10.3390/ijms24065109
Biomedicines. 2023 Mar 13. pii: 887. [Epub ahead of print]11(3):

The Impact of Artificial Intelligence in the Odyssey of Rare Diseases.

Anna Visibelli, Bianca Roncaglia, Ottavia Spiga, Annalisa Santucci.

  Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify patterns and associations that would be difficult or impossible for human analysts to detect. Predictive modeling techniques, such as deep learning, have been used to forecast the progression of rare diseases, enabling the development of more targeted treatments. Moreover, AI has also shown promise in the field of drug development for rare diseases with the identification of subpopulations of patients who may be most likely to respond to a particular drug. This review aims to highlight the achievements of AI algorithms in the study of rare diseases in the past decade and advise researchers on which methods have proven to be most effective. The review will focus on specific rare diseases, as defined by a prevalence rate that does not exceed 1-9/100,000 on Orphanet, and will examine which AI methods have been most successful in their study. We believe this review can guide clinicians and researchers in the successful application of ML in rare diseases.

Keywords:  artificial intelligence; data analysis; machine learning; precision medicine; rare disease

DOI:  https://doi.org/10.3390/biomedicines11030887
Front Neurol. 2023 ;14 1098454

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration.

Aleksandar Videnovic, Helle C V Pfeiffer, Anna Tylki-Szymańska, Elizabeth Berry-Kravis, Fatih Ezgü, Jitendra Ganju, Agnieszka Jurecka, Anthony E Lang.

  Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

Keywords:  clinical trial design; inborn errors of metabolism; movement disorders; orphan disease; ultra-rare disease

DOI:  https://doi.org/10.3389/fneur.2023.1098454
J Peripher Nerv Syst. 2023 Mar 25.

Charcot-Marie-Tooth neuropathies: Current gene therapy advances and the route toward translation.

Marina Stavrou, Alexia Kagiava, Irene Sargiannidou, Elena Georgiou, Kleopas A Kleopa.

  Charcot-Marie-Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene- and disease- and even mutation-specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular-genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non-human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale-up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.

Keywords:  Charcot-Marie-Tooth disease; axonal degeneration; gene therapy; inherited neuropathy; mouse models; non human primates

DOI:  https://doi.org/10.1111/jns.12543
J Nutr Biochem. 2023 Mar 27. pii: S0955-2863(23)00070-0. [Epub ahead of print] 109337

Glycophagy mediated glucose-induced changes of hepatic glycogen metabolism via OGT1-AKT1-FOXO1Ser238 pathway.

Li-Xiang Wu, Yi-Chuang Xu, Kostas Pantopoulos, Xiao-Ying Tan, Xiao-Lei Wei, Hua Zheng, Zhi Luo.

  Glycophagy is the autophagy degradation of glycogen. However, the regulatory mechanisms for glycophagy and glucose metabolism remain unexplored. Herein, we demonstrated that high-carbohydrate diet (HCD) and high glucose (HG) incubation induced glycogen accumulation, AKT1 expression and AKT1-dependent phosphorylation of forkhead transcription factor O1 (FOXO1) at Ser238 in the liver tissues and hepatocytes. The glucose-induced FOXO1 phosphorylation at Ser238 prevents FOXO1 entry into the nucleus and the recruitment to the gabarapl1 promoter, reduces the gabarapl1 promoter activity, and inhibits glycophagy and glucose production. The glucose-dependent O-GlcNAcylation of AKT1 by OGT1 enhances the stability of AKT1 protein and promotes its binding with FOXO1. Moreover, the glycosylation of AKT1 is crucial for promoting FOXO1 nuclear translocation and inhibiting glycophagy. Our studies elucidate a novel mechanism for glycophagy inhibition by high carbohydrate and glucose via OGT1-AKT1-FOXO1Ser238 pathway in the liver tissues and hepatocytes, which provides critical insights into potential intervention strategies for glycogen storage disorders in vertebrates, as well as human beings.

Keywords:  Carbohydrate metabolism; Glycophagy; O-GlcNAcylation; Phosphorylation; Signaling pathway

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109337
J Pers Med. 2023 Feb 26. pii: 420. [Epub ahead of print]13(3):

Orphan Drugs in Neurology-A Narrative Review.

Carmen Adella Sirbu, Raluca Ivan, Francois Jerome Authier, Florentina Ionita-Radu, Dragos Catalin Jianu, Octavian Vasiliu, Ciprian Constantin, Sorin Tuță.

   BACKGROUND AND AIMS: Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment. With this paper, we aim to present some of the orphan neurological diseases for which new drugs have been developed lately.
METHODS: We have conducted a literature review of the papers concerning rare diseases and their treatment, and we have analyzed the existing studies for each orphan drug. For this purpose, we have used the Google Scholar search engine and the Orphanet. We have selected the studies published in the last 15 years.
RESULTS: Since the formation of the National Organization for Rare Diseases, the Orphan Drug Act, and the National Institutes of Health Office of Rare Diseases, pharmacological companies have made a lot of progress concerning the development of new drugs. Therefore, diseases that until recently were without therapeutic solutions benefit today from personalized treatment. We have detailed in our study over 15 neurological and systemic diseases with neurological implications, for which the last 10-15 years have brought important innovations regarding their treatment.
CONCLUSIONS: Many steps have been taken towards the treatment of these patients, and the humanity and professionalism of the pharmaceutical companies, along with the constant support of the patient's associations for rare diseases, have led to the discovery of new treatments and useful future findings.

Keywords:  acute hepatic porphyria; duchenne muscular dystrophy; fabry disease; hereditary transthyretin-mediated amyloidosis; myasthenia; narcolepsy; non-dystrophic myotonias; orphan diseases; pompe disease; spinal muscular atrophy

DOI:  https://doi.org/10.3390/jpm13030420
Methods Mol Biol. 2023 ;2640 129-142

In Vitro Maturation of Human Pluripotent Stem Cell-Derived Myotubes.

Ricardo Mondragon-Gonzalez, Sridhar Selvaraj, Rita C R Perlingeiro.

  Pluripotent stem cells have a multitude of potential applications in the areas of disease modeling, drug screening, and cell-based therapies for genetic diseases, including muscular dystrophies. The advent of induced pluripotent stem cell technology allows for the facile derivation of disease-specific pluripotent stem cells for any given patient. Targeted in vitro differentiation of pluripotent stem cells into the muscle lineage is a key step to enable all these applications. Transgene-based differentiation using conditional expression of the transcription factor PAX7 leads to the efficient derivation of an expandable and homogeneous population of myogenic progenitors suitable for both in vitro and in vivo applications. Here, we describe an optimized protocol for the derivation and expansion of myogenic progenitors from pluripotent stem cells using conditional expression of PAX7. Importantly, we further describe an optimized procedure for the terminal differentiation of myogenic progenitors into more mature myotubes, which are better suited for in vitro disease modeling and drug screening studies.

Keywords:  Induced pluripotent stem (iPS) cells; Myogenic differentiation; Myotubes; PAX7; Small molecules

DOI:  https://doi.org/10.1007/978-1-0716-3036-5_10
Int J Environ Res Public Health. 2023 Mar 08. pii: 4732. [Epub ahead of print]20(6):

Enhancing Equitable Access to Rare Disease Diagnosis and Treatment around the World: A Review of Evidence, Policies, and Challenges.

Takeya Adachi, Ayman W El-Hattab, Ritu Jain, Katya A Nogales Crespo, Camila I Quirland Lazo, Maurizio Scarpa, Marshall Summar, Duangrurdee Wattanasirichaigoon.

  This document provides a comprehensive summary of evidence on the current situation of rare diseases (RDs) globally and regionally, including conditions, practices, policies, and regulations, as well as the challenges and barriers faced by RD patients, their families, and caregivers. The document builds on a review of academic literature and policies and a process of validation and feedback by a group of seven experts from across the globe. Panelists were selected based on their academic merit, expertise, and knowledge regarding the RD environment. The document is divided into five main sections: (1) methodology and objective; (2) background and context; (3) overview of the current situation and key challenges related to RDs covering six dimensions: burden of disease, patient journey, social impact, disease management, RD-related policies, and research and development; (4) recommendations; and (5) conclusions. The recommendations are derived from the discussion undertaken by the experts on the findings of this review and provide a set of actionable solutions to the challenges and barriers to improving access to RD diagnosis and treatment around the world. The recommendations can support critical decision-making, guiding efforts by a broad range of RDs stakeholders, including governments, international organizations, manufacturers, researchers, and patient advocacy groups.

Keywords:  burden of disease; disease management; health equity; health policies; patient journey; rare diseases; social impact

DOI:  https://doi.org/10.3390/ijerph20064732
Circ Res. 2023 Mar 31. 132(7): 882-898

Ketones and the Heart: Metabolic Principles and Therapeutic Implications.

Timothy R Matsuura, Patrycja Puchalska, Peter A Crawford, Daniel P Kelly.

  The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

Keywords:  3-hydroxybutyric acid; acetoacetate; diet, ketogenic; fatty acid oxidation; heart failure; hypertrophy; ketone bodies

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.321872
Genes (Basel). 2023 Mar 16. pii: 727. [Epub ahead of print]14(3):

Pathogenic Variants Associated with Rare Monogenic Diseases Established in Ancient Neanderthal and Denisovan Genome-Wide Data.

Draga Toncheva, Maria Marinova, Todor Chobanov, Dimitar Serbezov.

  Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.

Keywords:  ancient DNA; genome-wide data; monogenic diseases

DOI:  https://doi.org/10.3390/genes14030727
Circ Genom Precis Med. 2023 Mar 29. e004104

Genetic Testing in Patients With Congenital Heart Disease: You Do No Harm When Using the Right Tools!

Julie De Backer, Laura Muiño Mosquera.



Keywords:  Editorials; caregivers; consensus; exome sequencing; genomics

DOI:  https://doi.org/10.1161/CIRCGEN.123.004104
Cardiovasc Diabetol. 2023 Mar 28. 22(1): 73

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.

Keshav Gopal, Qutuba G Karwi, Seyed Amirhossein Tabatabaei Dakhili, Cory S Wagg, Liyan Zhang, Qiuyu Sun, Christina T Saed, Sai Panidarapu, Riccardo Perfetti, Ravichandran Ramasamy, John R Ussher, Gary D Lopaschuk.

   BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism.
METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism.
RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min-1 g dry wt-1 in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy.
CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.

Keywords:  AT-001; Aldose reductase; Diabetic cardiomyopathy; Diastolic dysfunction; Fatty acid oxidation

DOI:  https://doi.org/10.1186/s12933-023-01811-w
Brain Sci. 2023 Mar 22. pii: 524. [Epub ahead of print]13(3):

Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges.

Jiafeng Chen, Lijuan Huang, Yue Yang, Wei Xu, Qingchun Qin, Rongxing Qin, Xiaojun Liang, Xinyu Lai, Xiaoying Huang, Minshan Xie, Li Chen.

  Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications.

Keywords:  mechanisms; microRNA; molecules; nervous system diseases; neurons; neuroscience; reprogramming; somatic cell; therapeutic; transcription factors

DOI:  https://doi.org/10.3390/brainsci13030524
Acta Pharm Sin B. 2023 Mar;13(3): 1028-1035

Mitochondrial transplantation as a promising therapy for mitochondrial diseases.

Tian-Guang Zhang, Chao-Yu Miao.

  Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.

Keywords:  Ethical issue; Mitochondria; Mitochondrial delivery; Mitochondrial disease; Mitochondrial isolation; Mitochondrial storage; Mitochondrial transplantation; Mitochondrial transplantation rejection

DOI:  https://doi.org/10.1016/j.apsb.2022.10.008
Prenat Diagn. 2023 Mar 25.

Gene Modification Therapies for Hereditary Diseases in the Fetus.

Citra N Z Mattar, Jerry Ky Chan, Mahesh Choolani.

Proof-of-principle disease models have demonstrated the feasibility of an intrauterine gene modification therapy (IUGT) approach to hereditary diseases as diverse as coagulation disorders, haemoglobinopathies, neurogenetic disorders, congenital metabolic and pulmonary diseases. Gene addition, requiring the delivery of an integrating or episomal transgene to the target cell nucleus to be transcribed, or gene editing, where the mutation is corrected within the gene of origin, have both been used successfully to increase normal protein production in a bid to reverse or arrest pathology in utero. While most experimental models have employed lentiviral, adenoviral, and adeno-associated viral vectors engineered to efficiently enter target cells, newer models have also demonstrated the applicability of non-viral lipid nanoparticles. Amelioration of pathology is dependent primarily on achieving sustained therapeutic transgene expression, silencing of transgene expression, production of neutralising antibodies, the dilutional effect of the recipient's growth on the mass of transduced cells, and the degree of pre-existing cellular damage. Safety assessment of any IUGT strategy will require long-term postnatal surveillance of both the fetal recipient and the maternal bystander, for cell and genome toxicity, oncogenic potential, immune-responsiveness, and germline mutation. In this review, we discuss advances in the field and the push towards clinical translation of IUGT. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/pd.6347
Cell Rep. 2023 Mar 20. pii: S2211-1247(23)00287-5. [Epub ahead of print] 112276

Stem cell-based modeling and single-cell multiomics reveal gene-regulatory mechanisms underlying human skeletal development.

Shoichiro Tani, Hiroyuki Okada, Shoko Onodera, Ryota Chijimatsu, Masahide Seki, Yutaka Suzuki, Xiaonan Xin, David W Rowe, Taku Saito, Sakae Tanaka, Ung-Il Chung, Shinsuke Ohba, Hironori Hojo.

  Although the skeleton is essential for locomotion, endocrine functions, and hematopoiesis, the molecular mechanisms of human skeletal development remain to be elucidated. Here, we introduce an integrative method to model human skeletal development by combining in vitro sclerotome induction from human pluripotent stem cells and in vivo endochondral bone formation by implanting the sclerotome beneath the renal capsules of immunodeficient mice. Histological and scRNA-seq analyses reveal that the induced bones recapitulate endochondral ossification and are composed of human skeletal cells and mouse circulatory cells. The skeletal cell types and their trajectories are similar to those of human embryos. Single-cell multiome analysis reveals dynamic changes in chromatin accessibility associated with multiple transcription factors constituting cell-type-specific gene-regulatory networks (GRNs). We further identify ZEB2, which may regulate the GRNs in human osteogenesis. Collectively, these results identify components of GRNs in human skeletal development and provide a valuable model for its investigation.

Keywords:  CP: Developmental biology; CP: Stem cell biology; ZEB2; gene regulatory networks; human pluripotent stem cells; single-cell multiome analysis; skeletal development; zinc finger E-box binding homeobox 2

DOI:  https://doi.org/10.1016/j.celrep.2023.112276
Hepatol Commun. 2023 04 01. pii: e0105. [Epub ahead of print]7(4):

Liver organoids: established tools for disease modeling and drug development.

Xi-Cheng Sun, De-Fu Kong, Jie Zhao, Klaas Nico Faber, Qiang Xia, Kang He.

In the past decade, liver organoids have evolved rapidly as valuable research tools, providing novel insights into almost all types of liver diseases, including monogenic liver diseases, alcohol-associated liver disease, metabolic-associated fatty liver disease, various types of (viral) hepatitis, and liver cancers. Liver organoids in part mimic the microphysiology of the human liver and fill a gap in high-fidelity liver disease models to a certain extent. They hold great promise to elucidate the pathogenic mechanism of a diversity of liver diseases and play a crucial role in drug development. Moreover, it is challenging but opportunistic to apply liver organoids for tailored therapies of various liver diseases. The establishment, applications, and challenges of different types of liver organoids, for example, derived from embryonic, adult, or induced pluripotent stem cells, to model different liver diseases, are presented in this review.

DOI: https://doi.org/10.1097/HC9.0000000000000105
Metabolites. 2023 Mar 18. pii: 447. [Epub ahead of print]13(3):

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives.

Marcello Cossu, Roberta Pintus, Marco Zaffanello, Michele Mussap, Fabiola Serra, Maria Antonietta Marcialis, Vassilios Fanos.

  The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022.

Keywords:  biomarkers; inborn errors of metabolism; metabolomic; newborn screening

DOI:  https://doi.org/10.3390/metabo13030447
Int J Mol Sci. 2023 Mar 14. pii: 5561. [Epub ahead of print]24(6):

Regulation of Adenine Nucleotide Metabolism by Adenylate Kinase Isozymes: Physiological Roles and Diseases.

Koichi Fujisawa.

  Adenylate kinase (AK) regulates adenine nucleotide metabolism and catalyzes the ATP + AMP ⇌ 2ADP reaction in a wide range of organisms and bacteria. AKs regulate adenine nucleotide ratios in different intracellular compartments and maintain the homeostasis of the intracellular nucleotide metabolism necessary for growth, differentiation, and motility. To date, nine isozymes have been identified and their functions have been analyzed. Moreover, the dynamics of the intracellular energy metabolism, diseases caused by AK mutations, the relationship with carcinogenesis, and circadian rhythms have recently been reported. This article summarizes the current knowledge regarding the physiological roles of AK isozymes in different diseases. In particular, this review focused on the symptoms caused by mutated AK isozymes in humans and phenotypic changes arising from altered gene expression in animal models. The future analysis of intracellular, extracellular, and intercellular energy metabolism with a focus on AK will aid in a wide range of new therapeutic approaches for various diseases, including cancer, lifestyle-related diseases, and aging.

Keywords:  ATP; adenine nucleotides; adenylate kinase; energy metabolism; enzyme

DOI:  https://doi.org/10.3390/ijms24065561
Pediatr Rep. 2023 Mar 10. 15(1): 227-236

Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry.

Faïza Meiouet, Sâad El Kabbaj, Rachid Abilkassem, François Boemer.

   BACKGROUND: Expanded newborn screening using tandem mass spectrometry (MS/MS) for inborn errors of metabolism (IEM), such as organic acidemias (OAs), fatty acid oxidation disorders (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in Africa. With this study, we aim to establish the disease spectrum and frequency of inborn errors of OAs, FAODs, and AAs in Morocco.
METHODS: Selective screening was performed among infants and children suspected to be affected with IEM between 2016 and 2021. Amino acids and acylcarnitines spotted on filter paper were analyzed using MS/MS.
RESULTS: Out of 1178 patients with a clinical suspicion, 137 (11.62%) were diagnosed with IEM, of which 121 (88.3%) patients suffered from amino acids disorders, 11 (8%) were affected by FAOD, and 5 (3.7%) by an OA.
CONCLUSIONS: This study shows that various types of IEM are also present in Morocco. Furthermore, MS/MS is an indispensable tool for early diagnosis and management of this group of disorders.

Keywords:  Morocco; amino acid disorders; fatty acid oxidation disorders; inborn errors of metabolism; organic acidemias; tandem mass spectrometry

DOI:  https://doi.org/10.3390/pediatric15010018
Metabolites. 2023 Mar 08. pii: 399. [Epub ahead of print]13(3):

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male.

Undiagnosed Diseases Network

  We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient's ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient's nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.

Keywords:  NADH deficiency; NADH metabolism; errors of metabolism; nicotinamide; nicotinamide N-methyltransferase; nicotinamide N-methyltransferase deficiency

DOI:  https://doi.org/10.3390/metabo13030399
Cell. 2023 Mar 30. pii: S0092-8674(23)00219-2. [Epub ahead of print]186(7): 1302-1304

Gene therapy for inborn errors of immunity: Base editing comes into play.

Harry L Malech, Luigi D Notarangelo.

CRISPR-Cas9-based base editing allows precise base editing to achieve conversion of adenosine to guanine or cytosine to thymidine. In this issue of Cell, McAuley et al. use adenine base editing to correct a single base-pair mutation causing human CD3δ deficiency, demonstrating superior efficiency of genetic correction with reduced undesired genetic alterations compared with standard CRISPR-Cas9 editing.

DOI: https://doi.org/10.1016/j.cell.2023.03.001
Hepatology. 2023 Apr 03.

Single-cell and spatially resolved transcriptomics for liver biology.

Ping Lin, Xi Yan, Siyu Jing, Yanhong Wu, Yiran Shan, Wenbo Guo, Jin Gu, Yu Li, Haibing Zhang, Hong Li.

Single-cell transcriptomics enables the identification of rare cell types and the inference of state transitions, and spatially resolved transcriptomics allows the quantification of cells and genes in the context of tissues. The recent progress in these new technologies is improving our understanding of the cell landscape and its roles in diseases. Here, we review key biological insights into liver homeostasis, development, regeneration, chronic liver disease and cancer obtained from single-cell and spatially resolved transcriptomics. We highlight recent progress in the liver cell atlas that characterizes the comprehensive cellular composition, diversity and function; the spatial architecture, such as liver zonation, cell communication and proximity; the cell identity conversion and cell-specific alterations that are associated with liver pathology; and new therapeutic targets. We further discuss outstanding challenges, advanced experimental technologies and computational methods helping to address these challenges.

DOI: https://doi.org/10.1097/HEP.0000000000000387
Int J Mol Sci. 2023 Mar 08. pii: 5188. [Epub ahead of print]24(6):

Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration.

Marcy Martin, Eric K N Gähwiler, Melanie Generali, Simon P Hoerstrup, Maximilian Y Emmert.

  The adult human heart cannot regain complete cardiac function following tissue injury, making cardiac regeneration a current clinical unmet need. There are a number of clinical procedures aimed at reducing ischemic damage following injury; however, it has not yet been possible to stimulate adult cardiomyocytes to recover and proliferate. The emergence of pluripotent stem cell technologies and 3D culture systems has revolutionized the field. Specifically, 3D culture systems have enhanced precision medicine through obtaining a more accurate human microenvironmental condition to model disease and/or drug interactions in vitro. In this study, we cover current advances and limitations in stem cell-based cardiac regenerative medicine. Specifically, we discuss the clinical implementation and limitations of stem cell-based technologies and ongoing clinical trials. We then address the advent of 3D culture systems to produce cardiac organoids that may better represent the human heart microenvironment for disease modeling and genetic screening. Finally, we delve into the insights gained from cardiac organoids in relation to cardiac regeneration and further discuss the implications for clinical translation.

Keywords:  cardiac organoids; cardiac regeneration; engineered heart tissue; pluripotent stem cells; precision medicine

DOI:  https://doi.org/10.3390/ijms24065188
J Mol Cell Cardiol. 2023 Mar 23. pii: S0022-2828(23)00054-8. [Epub ahead of print]

Cellular reprogramming of fibroblasts in heart regeneration.

Congwu Chi, Kunhua Song.

  Myocardial infarction causes the loss of cardiomyocytes and the formation of cardiac fibrosis due to the activation of cardiac fibroblasts, leading to cardiac dysfunction and heart failure. Unfortunately, current therapeutic interventions can only slow the disease progression. Furthermore, they cannot fully restore cardiac function, likely because the adult human heart lacks sufficient capacity to regenerate cardiomyocytes. Therefore, intensive efforts have focused on developing therapeutics to regenerate the damaged heart. Several strategies have been intensively investigated, including stimulation of cardiomyocyte proliferation, transplantation of stem cell-derived cardiomyocytes, and conversion of fibroblasts into cardiac cells. Resident cardiac fibroblasts are critical in the maintenance of the structure and contractility of the heart. Fibroblast plasticity makes this type of cells be reprogrammed into many cell types, including but not limited to induced pluripotent stem cells, induced cardiac progenitor cells, and induced cardiomyocytes. Fibroblasts have become a therapeutic target due to their critical roles in cardiac pathogenesis. This review summarizes the reprogramming of fibroblasts into induced pluripotent stem cell-derived cardiomyocytes, induced cardiac progenitor cells, and induced cardiomyocytes to repair a damaged heart, outlines recent findings in utilizing fibroblast-derived cells for heart regeneration, and discusses the limitations and challenges.

Keywords:  Cellular reprogramming; Fibroblast cell fate switch; Heart regeneration; iCMs; iCPCs; iECs; iPSC-CMs; iSMCs; rCVT

DOI:  https://doi.org/10.1016/j.yjmcc.2023.03.009
J Mol Cell Cardiol. 2023 Mar 23. pii: S0022-2828(23)00053-6. [Epub ahead of print]

Direct cardiac reprogramming: A new technology for cardiac repair.

Paige E Brlecic, Clark A Bonham, Todd K Rosengart, Megumi Mathison.

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide, with myocardial infarctions being amongst the deadliest manifestations. Reduced blood flow to the heart can result in the death of cardiac tissue, leaving affected patients susceptible to further complications and recurrent disease. Further, contemporary management typically involves a pharmacopeia to manage the metabolic conditions contributing to atherosclerotic and hypertensive heart disease, rather than regeneration of the damaged myocardium. With modern healthcare extending lifespan, a larger demographic will be at risk for heart disease, driving the need for novel therapeutics that surpass those currently available in efficacy. Transdifferentiation and cellular reprogramming have been looked to as potential methods for the treatment of diseases throughout the body. Specifically targeting the fibrotic cells in cardiac scar tissue as a source to be reprogrammed into induced cardiomyocytes remains an appealing option. This review aims to highlight the history of and advances in cardiac reprogramming and describe its translational potential as a treatment for cardiovascular disease.

DOI: https://doi.org/10.1016/j.yjmcc.2023.03.008
Int J Neonatal Screen. 2023 Mar 17. pii: 15. [Epub ahead of print]9(1):

Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm.

Giancarlo la Marca, Rachel S Carling, Stuart J Moat, Raquel Yahyaoui, Enzo Ranieri, James R Bonham, Peter C J I Schielen.

  In 1963, Robert Guthrie's pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, 'second-tier' methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening.

Keywords:  2nd-tier testing; NGS in NBS; SCID screening; biochemical analysis; cystic fibrosis screening; metabolomics; neonatal screening; next-generation sequencing; proteomics; quality control

DOI:  https://doi.org/10.3390/ijns9010015
Biol Futur. 2023 Mar 31.

The importance of pseudouridylation: human disorders related to the fifth nucleoside.

Tália Magdolna Keszthelyi, Kálmán Tory.

  Pseudouridylation is one of the most abundant RNA modifications in eukaryotes, making pseudouridine known as the "fifth nucleoside." This highly conserved alteration affects all non-coding and coding RNA types. Its role and importance have been increasingly widely researched, especially considering that its absence or damage leads to serious hereditary diseases. Here, we summarize the human genetic disorders described to date that are related to the participants of the pseudouridylation process.

Keywords:  Pseudouridine; Pseudouridylation; RNA modification

DOI:  https://doi.org/10.1007/s42977-023-00158-3