bims-meglyc 2023-01-29 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–01–29
nineteen papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Higher frequency of TEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation.
Identifying Genetic Regulators of Protein-Glycan Interactions with Genome-Wide CRISPR Screening.
Structural identification of N-glycan isomers using logically derived sequence tandem mass spectrometry.
Breakthrough of glycobiology in the 21st century.
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up.
International Experiences and Made-in-Canada "Social Pharmaceutical Innovations" as Responses to Challenges Facing Drugs for Rare Diseases.
Analysis of the expression and distribution of protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 in the normal adult mouse brain.
Exome/Genome Sequencing in Undiagnosed Syndromes.
Changes of energy metabolism in failing heart and its regulation by SIRT3.
Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms.
Specific, Fair and Transparent: A Canadian Process for Funding Drugs for Rare Diseases.
Advancements in modelling human blood brain-barrier on a chip.
Mitochondria metabolism sets the species-specific tempo of neuronal development.
THE EVOLVING ROLE OF MEDICAL GENETICISTS IN THE ERA OF GENE THERAPY: AN URGENCY TO PREPARE.
Gene-targeted therapies: Towards equitable development, diagnosis, and access.
RNA therapeutics in the clinic.
Competing Values, Competing Claims: Diversity among Patient Advocates Who Intervene to Shape Policies on Drugs for Rare Diseases.
Mitochondrial NAD kinase in health and disease.
Expensive Drugs for Rare Diseases: "Canada, We Have a Problem Here".

Eur J Med Genet. 2023 Jan 24. pii: S1769-7212(23)00015-0. [Epub ahead of print] 104709

Higher frequency of TEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation.

Agata Fiumara, Annamaria Sapuppo, Lorenzo Ferri, Alessia Arena, Adriana Prato, Domenico Garozzo, Luisa Sturiale, Amelia Morrone, Rita Barone.

  Congenital disorders of glycosylation (CDG) are genetic multisystem diseases, characterized by defective glycoconjugate synthesis. A small number of CDG with isolated liver damage have been described, such as TMEM199-CDG, a non-encephalopathic liver disorder with Wilson disease-like phenotype. Only eight patients with TMEM199-CDG have been described including seven Europeans (originating from Greece and Italy) and one Chinese. Three patients from southern Italy (Campania) shared the same known missense mutation pathogenetic variant NM_152464.3:c. 92G > C (p.Arg31Pro), also found in a Greek patient. Here we report a new patient from southern Italy (Sicily), with a homozygous c.92G > C p.(Arg31Pro) variant in TMEM199. The patient's phenotype is characterized by mild non-progressive hepatopathy with a normal hepatic echo structure. A persistent increase in serum transaminases, total and low-density lipoprotein cholesterol and low serum ceruloplasmin and copper levels and normal urinary copper excretion were observed. Matrix-assisted laser desorption/ionization mass spectrometry analyses showed abnormal N- and O- protein glycosylation, indicative of a Golgi processing defect and supporting the function of TMEM199 in maintaining Golgi homeostasis. TMEM199-CDG is an ultra-rare CDG relatively frequent in the southern Mediterranean area (7 in 9 patients, 77%). It is mainly associated with the c.92G > C (p.Arg31Pro) pathogenetic allele globally reported in 4 out of 7 families (57%), including one from Greece and three unrelated families from southern Italy. The almost uniform clinical phenotype described in patients with TMEM199-CDG appears to reflect a higher prevalence of the same variant in patients from the southern Mediterranean area.

Keywords:  CDG; Golgi glycosylation defect; Liver disease; TMEM199; c.92G>C variant

DOI:  https://doi.org/10.1016/j.ejmg.2023.104709
Curr Protoc. 2023 Jan;3(1): e646

Identifying Genetic Regulators of Protein-Glycan Interactions with Genome-Wide CRISPR Screening.

Vignesh Krishnamoorthy, John Daly, Simon Wisnovsky.

  Glycans are carbohydrate molecules appended to proteins and lipids on the surface of all living cells. Glycans play key roles in a wide array of biological processes, and structural changes in cell-surface glycosylation patterns have been connected to pathogenesis of several diseases. In particular, cancer cells frequently upregulate expression of glycans that bind to inhibitory receptors (lectins) on immune cells. These glycosylated antigens systematically inhibit immune activity and protect cancer cells from immune surveillance. Understanding how cancer cells generate these glycan ligands can thus lead to identification of novel druggable targets for therapeutic intervention. However, glycan ligand biosynthesis is subject to extremely complex genetic regulation, making it difficult to identify the key genes involved in production of immune-regulatory glycan antigens. In a recent publication, we described a CRISPR/Cas9 screening approach to identify genes that drive synthesis of ligands for glycan-binding immune receptors. Here, we outline a detailed, step-by-step protocol for completing this type of genome-wide screen. Our protocol produces a genome-wide atlas of all genes whose expression is required for cell-surface binding of a recombinant immune lectin. This dataset can be used both to identify novel ligands for immune lectins and annotate regulatory genes that drive changes in cancer-associated glycosylation. Our protocol serves as a general resource for researchers interested in the detailed study of cancer glyco-immunology. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Generation of a genome-wide CRISPR library using lentiviral transduction Support Protocol: Generation of dCas9KRAB-expressing K-562 cells Basic Protocol 2: Staining of genome-wide CRISPR libraries with Siglec-Fc reagents and fluorescence-activated cell sorting Basic Protocol 3: Library amplification and sequencing Basic Protocol 4: Data analysis and hit identification.

Keywords:  CRISPR screening; cancer; glycobiology; glycomics; immunology

DOI:  https://doi.org/10.1002/cpz1.646
Commun Chem. 2021 Jun 17. 4(1): 92

Structural identification of N-glycan isomers using logically derived sequence tandem mass spectrometry.

Chia Yen Liew, Chu-Chun Yen, Jien-Lian Chen, Shang-Ting Tsai, Sujeet Pawar, Chung-Yi Wu, Chi-Kung Ni.

N-linked glycosylation is one of the most important protein post-translational modifications. Despite the importance of N-glycans, the structural determination of N-glycan isomers remains challenging. Here we develop a mass spectrometry method, logically derived sequence tandem mass spectrometry (LODES/MSn), to determine the structures of N-glycan isomers that cannot be determined using conventional mass spectrometry. In LODES/MSn, the sequences of successive collision-induced dissociation are derived from carbohydrate dissociation mechanisms and apply to N-glycans in an ion trap for structural determination. We validate LODES/MSn using synthesized N-glycans and subsequently applied this method to N-glycans extracted from soybean, ovalbumin, and IgY. Our method does not require permethylation, reduction, and labeling of N-glycans, or the mass spectrum databases of oligosaccharides and N-glycan standards. Moreover, it can be applied to all types of N-glycans (high-mannose, hybrid, and complex), as well as the N-glycans degraded from larger N-glycans by any enzyme or acid hydrolysis.

DOI: https://doi.org/10.1038/s42004-021-00532-z
Front Immunol. 2022 ;13 1071360

Breakthrough of glycobiology in the 21st century.

Gehendra Mahara, Cuihong Tian, Xiaojia Xu, Jinxiu Zhu.

  As modern medicine began to emerge at the turn of the 20th century, glycan-based therapies advanced. DNA- and protein-centered therapies became widely available. The research and development of structurally defined carbohydrates have led to new tools and methods that have sparked interest in the therapeutic applications of glycans. One of the latest omics disciplines to emerge in the contemporary post-genomics age is glycomics. In addition, to providing hope for patients and people with different health conditions through a deeper understanding of the mechanisms of common complex diseases, this new specialty in system sciences has much to offer to communities involved in the development of diagnostics and therapeutics in medicine and life sciences.This review focuses on recent developments that have pushed glycan-based therapies into the spotlight in medicine and the technologies powering these initiatives, which we can take as the most significant success of the 21st century.

Keywords:  carbohydrate; drug development; glycan; glycobiology; nanotechnology; vaccine

DOI:  https://doi.org/10.3389/fimmu.2022.1071360
Crit Rev Clin Lab Sci. 2023 Jan 24. 1-20

Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up.

Abraham J Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch.

  The currently available biomarkers generally lack the specificity and sensitivity needed for the diagnosis and follow-up of patients with mitochondrial diseases (MDs). In this group of rare genetic disorders (mutations in approximately 350 genes associated with MDs), all clinical presentations, ages of disease onset and inheritance types are possible. Blood, urine, and cerebrospinal fluid surrogates are well-established biomarkers that are used in clinical practice to assess MD. One of the main challenges is validating specific and sensitive biomarkers for the diagnosis of disease and prediction of disease progression. Profiling of lactate, amino acids, organic acids, and acylcarnitine species is routinely conducted to assess MD patients. New biomarkers, including some proteins and circulating cell-free mitochondrial DNA, with increased diagnostic specificity have been identified in the last decade and have been proposed as potentially useful in the assessment of clinical outcomes. Despite these advances, even these new biomarkers are not sufficiently specific and sensitive to assess MD progression, and new biomarkers that indicate MD progression are urgently needed to monitor the success of novel therapeutic strategies. In this report, we review the mitochondrial biomarkers that are currently analyzed in clinical laboratories, new biomarkers, an overview of the most common laboratory diagnostic techniques, and future directions regarding targeted versus untargeted metabolomic and genomic approaches in the clinical laboratory setting. Brief descriptions of the current methodologies are also provided.

Keywords:  Mitochondrial diseases; biomarkers; laboratory diagnosis; mass spectrometry; metabolomics

DOI:  https://doi.org/10.1080/10408363.2023.2166013
Healthc Pap. 2023 Jan;pii: hcpap.2023.26993. [Epub ahead of print]21(1): 66-72

International Experiences and Made-in-Canada "Social Pharmaceutical Innovations" as Responses to Challenges Facing Drugs for Rare Diseases.

Conor M W Douglas.

Significant challenges are associated with the availability of and access to treatments for rare diseases. In this issue, Sirrs et al. (2023) frame challenges in terms of evidence, economics and ethics and describe how they manifest in the Canadian context. This short response paper argues that although interesting initiatives exist internationally to deal with some of these challenges, a plug-and-play approach will not suffice given the particularities of the Canadian system. Rather than seeking international lessons on how to deal with Canadian challenges, the emerging interdisciplinary framework of social pharmaceutical innovation is advanced here as a whole-systems approach that stands to address interconnected components of the rare disease ecosystem, and in doing so, a made-in-Canada approach is advocated for.

DOI: https://doi.org/10.12927/hcpap.2023.26993
Front Neuroanat. 2022 ;16 1043924

Analysis of the expression and distribution of protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 in the normal adult mouse brain.

Hanxiao Jiang, Yuxue Feng, Guiqiong He, Yuanjie Liu, Xiaofeng Li.

   Introduction: Protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is crucial for the elongation of O-mannosyl glycans. Mutations in POMGNT1 cause muscle-eye-brain (MEB) disease, one of the main features of which is anatomical aberrations in the brain. A growing number of studies have shown that defects in POMGNT1 affect neuronal migration and distribution, disrupt basement membranes, and misalign Cajal-Retzius cells. Several studies have examined the distribution and expression of POMGNT1 in the fetal or neonatal brain for neurodevelopmental studies in the mouse or human brain. However, little is known about the neuroanatomical distribution and expression of POMGNT1 in the normal adult mouse brain.
Methods: We analyzed the expression of POMGNT1 mRNA and protein in the brains of various neuroanatomical regions and spinal cords by western blotting and RT-qPCR. We also detected the distribution profile of POMGnT1 in normal adult mouse brains by immunohistochemistry and double-immunofluorescence.
Results: In the present study, we found that POMGNT1-positive cells were widely distributed in various regions of the brain, with high levels of expression in the cerebral cortex and hippocampus. In terms of cell type, POMGNT1 was predominantly expressed in neurons and was mainly enriched in glutamatergic neurons; to a lesser extent, it was expressed in glial cells. At the subcellular level, POMGNT1 was mainly co-localized with the Golgi apparatus, but expression in the endoplasmic reticulum and mitochondria could not be excluded.
Discussion: The present study suggests that POMGNT1, although widely expressed in various brain regions, may has some regional and cellular specificity, and the outcomes of this study provide a new laboratory basis for revealing the possible involvement of POMGNT1 in normal physiological functions of the brain from a morphological perspective.

Keywords:  Golgi; O-mannosylation; POMGNT1; adult mouse; brain distribution; neurons

DOI:  https://doi.org/10.3389/fnana.2022.1043924
Annu Rev Med. 2023 Jan 27. 74 489-502

Exome/Genome Sequencing in Undiagnosed Syndromes.

Jennifer A Sullivan, Kelly Schoch, Rebecca C Spillmann, Vandana Shashi.

  Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain undiagnosed with current NGS. Improved NGS technology has resulted in long-read sequencing, which may resolve diagnoses in some patients who do not obtain a diagnosis with current short-read ES and GS, but its effectiveness is unclear, and it is expensive. Other challenges that persist include the resolution of variants of uncertain significance, the urgent need for patients with ultrarare disorders to have access to therapeutics, the need for equity in patient access to NGS-based testing, and the study of ethical concerns. However, the outlook for undiagnosed disease resolution is bright, due to continual advancements in the field.

Keywords:  Mendelian diseases; exome sequencing; genome sequencing; next-generation sequencing; rare/ultrarare diseases; undiagnosed diseases

DOI:  https://doi.org/10.1146/annurev-med-042921-110721
Heart Fail Rev. 2023 Jan 28.

Changes of energy metabolism in failing heart and its regulation by SIRT3.

Xiao Wang, Yuting Huang, Kai Zhang, Feng Chen, Tong Nie, Yun Zhao, Feng He, Jingyu Ni.

  Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.

Keywords:  Fatty acids; Glucose; Heart failure; Ketone body; Mitochondrion; SIRT3

DOI:  https://doi.org/10.1007/s10741-023-10295-5
Front Pharmacol. 2022 ;13 1095923

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms.

Pascal Büttiker, Simon Weissenberger, Tobias Esch, Martin Anders, Jiri Raboch, Radek Ptacek, Richard M Kream, George B Stefano.

  Mitochondria are complex endosymbionts that evolved from primordial purple nonsulfur bacteria. The incorporation of bacteria-derived mitochondria facilitates a more efficient and effective production of energy than what could be achieved based on previous processes alone. In this case, endosymbiosis has resulted in the seamless coupling of cytochrome c oxidase and F-ATPase to maximize energy production. However, this mechanism also results in the generation of reactive oxygen species (ROS), a phenomenon that can have both positive and negative ramifications on the host. Recent studies have revealed that neuropsychiatric disorders have a pro-inflammatory component in which ROS is capable of initiating damage and cognitive malfunction. Our current understanding of cognition suggests that it is the product of a neuronal network that consumes a substantial amount of energy. Thus, alterations or perturbations of mitochondrial function may alter not only brain energy supply and metabolite generation, but also thought processes and behavior. Mitochondrial abnormalities and oxidative stress have been implicated in several well-known psychiatric disorders, including schizophrenia (SCZ) and bipolar disorder (BPD). As cognition is highly energy-dependent, we propose that the neuronal pathways underlying maladaptive cognitive processing and psychiatric symptoms are most likely dependent on mitochondrial function, and thus involve brain energy translocation and the accumulation of the byproducts of oxidative stress. We also hypothesize that neuropsychiatric symptoms (e.g., disrupted emotional processing) may represent the vestiges of an ancient masked evolutionary response that can be used by both hosts and pathogens to promote self-repair and proliferation via parasitic and/or symbiotic pathways.

Keywords:  HIV-1; SARS-CoV-2; bipolar disorder; depression; mitochondria; reactive nitrogen species; reactive oxygen species; schizophrenia

DOI:  https://doi.org/10.3389/fphar.2022.1095923
Healthc Pap. 2023 Jan;pii: hcpap.2023.26999. [Epub ahead of print]21(1): 28-33

Specific, Fair and Transparent: A Canadian Process for Funding Drugs for Rare Diseases.

Helen Stevenson.

In Canada, the focus on value for money and evaluating efficacy according to traditional ways has presented challenges to the funding of drugs for rare diseases (DRDs). This commentary validates and extends two worthy recommendations from the lead paper in this issue of Healthcare Papers (Sirrs et al. 2023). The paper's first recommendation, for a pan-Canadian approach for collecting evidentiary data, is critical. In the commentary, I add to this finding by suggesting that we enable patients to track and measure their response to treatment through data capture. The second recommendation is a pan-Canadian framework for funding DRDs. I extend the recommendation with an argument for public and private payer guidance as well as a fair and transparent funding framework solely for DRDs.

DOI: https://doi.org/10.12927/hcpap.2023.26999
Biofabrication. 2023 Jan 23.

Advancements in modelling human blood brain-barrier on a chip.

Vita Guarino, Alessandra Zizzari, Monica Bianco, Giuseppe Gigli, Lorenzo Moroni, Valentina Arima.

  The human Blood Brain Barrier (hBBB) is a complex cellular architecture separating the blood from the brain parenchyma. Its integrity and perfect functionality are essential for preventing that neurotoxic plasma components and pathogens enter the brain. Although vital for preserving the correct brain activity, the low permeability of hBBB represents a huge impediment to treat mental and neurological disorders or to adress brain tumors. Indeed, the vast majority of potential drug treatments are unable to reach the brain crossing the hBBB. On the other hand, hBBB integrity can be damaged or its permeability increas as result of infections or in presence of neurodegenerative diseases. Current in vitro systems and in vivo animal models used to study the molecular/drug transport mechanism through the hBBB have several intrinsic limitations that are difficult to be overcome. In this scenario, Organ-on-Chip (OoC) models based on microfluidic technologies are considered promising innovative platforms that combine the handiness of an in vitro model with the complexity of a living organ, while reducing time and costs. In this review, we focus on recent advances in OoCs for developing hBBB models, with the aim of providing the reader a critical overview of the main guidelines to design and manufacture a hBBB-on-chip, featuring chip areas able to mimick the "blood side" and "brain side", to choose the cells types that are both representative and convenient, and to adequatly evaluate the barrier integrity, stability, and functionality.

Keywords:  Blood Brain Barrier; In vitro models; Microfluidics; Organ-on-Chip

DOI:  https://doi.org/10.1088/1758-5090/acb571
Science. 2023 Jan 27. eabn4705

Mitochondria metabolism sets the species-specific tempo of neuronal development.

Ryohei Iwata, Pierre Casimir, Emir Erkol, Leïla Boubakar, Mélanie Planque, Isabel M Gallego López, Martyna Ditkowska, Vaiva Gaspariunaite, Sofie Beckers, Daan Remans, Katlijn Vints, Anke Vandekeere, Suresh Poovathingal, Matthew Bird, Nikky Corthout, Pieter Vermeersch, Sébastien Carpentier, Kristofer Davie, Massimiliano Mazzone, Natalia V Gounko, Stein Aerts, Bart Ghesquière, Sarah-Maria Fendt, Pierre Vanderhaeghen.

Neuronal development in the human cerebral cortex is considerably prolonged compared to that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.

DOI: https://doi.org/10.1126/science.abn4705
Genet Med. 2023 Jan 19. pii: S1098-3600(23)00028-X. [Epub ahead of print] 100022

THE EVOLVING ROLE OF MEDICAL GENETICISTS IN THE ERA OF GENE THERAPY: AN URGENCY TO PREPARE.

Jerry Vockley, Nicola Brunetti-Pierri, Wendy K Chung, Angus J Clarke, Nina Gold, Robert C Green, Stephen Kagan, Tara Moroz, Christian P Schaaf, Martin Schulz, Elfride De Baere.

  By 2030, it is estimated that at least 30 non-oncology gene therapies will be approved in the United States alone. These therapies could be used to treat up to 50,000 patients annually and have the potential to result in major shifts in disease management pathways. Medical geneticists have well-established roles in the direct management of many rare genetic diseases and often provide support in the diagnosis and care of patients with such diseases. Because an increasing number of gene therapies are likely to become available over the next decade, there is a need to better define the role of medical geneticists within current and future gene therapy pathways and prepare for their expected role within the context of this new treatment paradigm. This commentary examines the current and potential future roles of medical geneticists in gene therapy and identifies specific needs that must be addressed for medical geneticists to assume an expanded leadership role in this area.

Keywords:  Gene therapy; Medical genetics education; Rare diseases

DOI:  https://doi.org/10.1016/j.gim.2023.100022
Am J Med Genet C Semin Med Genet. 2023 Jan 23.

Gene-targeted therapies: Towards equitable development, diagnosis, and access.

Amy M Gaviglio, Mark W Skinner, Lily J Lou, Richard S Finkel, Erika F Augustine, Aaron J Goldenberg.

Genomic and gene-targeted therapies hold great promise in addressing the global issue of rare diseases. To achieve this promise, however, it is critical the twin goals of equity in access to testing and diagnosis, and equity in access to therapy be considered early in the life cycle of development and implementation. Rare disease researchers and clinicians must simultaneously recognize the life-altering potential of early diagnosis and administration of gene-targeted therapeutics while acknowledging that not everyone who experiences a rare disease and needs these therapies will be able to afford or access them. Achieving equity in the development of and access to gene-targeted therapies will not only require innovations in research, clinical, regulatory, and reimbursement frameworks, but will also necessitate increased attention to the ethical, legal, and social implications when establishing research paradigms and the translation of research results into novel interventions for rare genetic diseases. This article highlights and discusses the growing importance and recognition of health equity across the spectrum of rare disease research and care delivery.

DOI: https://doi.org/10.1002/ajmg.c.32032
Bioeng Transl Med. 2023 Jan;8(1): e10374

RNA therapeutics in the clinic.

Alexander Curreri, Disha Sankholkar, Samir Mitragotri, Zongmin Zhao.

  Ribonucleic acid (RNA) therapeutics are being actively researched as a therapeutic modality in preclinical and clinical studies. They have become one of the most ubiquitously known and discussed therapeutics in recent years in part due to the ongoing coronavirus pandemic. Since the first approval in 1998, research on RNA therapeutics has progressed to discovering new therapeutic targets and delivery strategies to enhance their safety and efficacy. Here, we provide an overview of the current clinically relevant RNA therapeutics, mechanistic basis of their function, and strategies to improve their clinical use. We discuss the 17 approved RNA therapeutics and perform an in-depth analysis of the 222 ongoing clinical trials, with an emphasis on their respective mechanisms and disease areas. We also provide perspectives on the challenges for clinical translation of RNA therapeutics and suggest potential strategies to address these challenges.

Keywords:  RNA therapeutic; antisense oligonucleotide; aptamer; clinical trial; gene therapy; lipid nanoparticle; mRNA; mRNA vaccine; siRNA

DOI:  https://doi.org/10.1002/btm2.10374
Healthc Pap. 2023 Jan;pii: hcpap.2023.26995. [Epub ahead of print]21(1): 52-58

Competing Values, Competing Claims: Diversity among Patient Advocates Who Intervene to Shape Policies on Drugs for Rare Diseases.

Sharon Batt.

Patient advocacy groups can push regulators to approve and pay for expensive drugs despite weak evidence of efficacy and/or safety. Advocacy organizations that critique high prices for rare diseases are less publicized but can also influence policy. The funding and relationships many groups have with the pharmaceutical industry may contribute to patient advocates' differing perspectives, but the leaders' values and experiences are an overlooked factor. We need to understand the dominant public-private partnership model of patient advocacy, its historical roots, justification and how key advocacy actors respond to it if we are to advance policies that will contain expensive drugs for rare diseases.

DOI: https://doi.org/10.12927/hcpap.2023.26995
Redox Biol. 2023 Jan 18. pii: S2213-2317(23)00014-9. [Epub ahead of print]60 102613

Mitochondrial NAD kinase in health and disease.

Ren Zhang, Kezhong Zhang.

  Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.

Keywords:  Antioxidation; MNADK; Mitochondria; NAD; NADK; NADK2; NADP

DOI:  https://doi.org/10.1016/j.redox.2023.102613
Healthc Pap. 2023 01;pii: hcpap.2023.27001. [Epub ahead of print]21(1): 4-8

Expensive Drugs for Rare Diseases: "Canada, We Have a Problem Here".

Joel Lexchin.

This issue of Healthcare Papers on expensive drugs for rare diseases (EDRDs) is very timely. According to the recently released Patented Medicine Prices Review Board's 2021 annual report, EDRDs have gone from 1.7% of pharmaceutical expenditures in 2012 to 12.2% in 2021, with a compound annual growth rate between 2012 and 2021 of 31.7% compared to 6.0% for all prescription medicines (PMPRB 2022).

DOI: https://doi.org/10.12927/hcpap.2023.27001