Review
Pharmacology & Pharmacy
Shikha Thakur, Apurba Sinhari, Priti Jain, Hemant R. Jadhav
Summary: It is estimated that only 2% of disease-modifying proteins have a druggable site that can be targeted by approved clinical candidates. Therefore, there is a need to develop therapeutics that can mitigate diseases caused by both druggable and non-druggable proteins or enzymes. Oligonucleotide therapeutics (OT) have shown potential in this regard, as they have improved selectivity and fewer off-target effects compared to small molecules. This review provides an overview of the past and present of OTs, as well as the current efforts to develop future therapeutics. It also discusses the challenges and advancements in OT drug delivery and the emerging approach of personalized treatment for rare and fatal diseases.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Bao T. Le, Sibasish Paul, Katarzyna Jastrzebska, Heera Langer, Marvin H. Caruthers, Rakesh N. Veedu
Summary: Recent advances in drug development have shown successful clinical translations using synthetic antisense oligonucleotides (ASOs). However, challenges such as large-scale production, toxicity, localization, and high cost of treatment need to be addressed. Thiomorpholino oligonucleotides (TMOs) have emerged as a potential solution, as they can be synthesized using solid-phase oligonucleotide synthesis methodologies. This study demonstrates that TMOs can efficiently induce exon skipping in a Duchenne muscular dystrophy (DMD) in vitro model and perform well at low concentrations, potentially improving the drug safety profile.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pharmacology & Pharmacy
Amin Kamel, Tate Owen, Izaiah Cole, Tania Valencia, Edmund C. Lee
Summary: PK and ADME properties of RGLS4326 were characterized in vivo and in vitro in mice and monkeys. RGLS4326 showed similar properties across different species, both in vivo and in vitro. Subcutaneous administration resulted in preferential exposure to the kidney, the intended target organ, for maximum target engagement. These findings support the interpretation of toxicology and efficacy studies and provide insight into the disposition of RGLS4326 in humans.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Hannah A. Blair
Summary: Tofersen (Qalsody(TM)) is an antisense oligonucleotide developed by Biogen to treat amyotrophic lateral sclerosis (ALS). It was approved in the USA on April 25, 2023, for the treatment of ALS in adults with a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the developmental milestones of tofersen leading to its first approval for ALS.
Review
Cell Biology
Lwanda Abonga Buthelezi, Shandre Pillay, Noxolo Nokukhanya Ntuli, Lorna Gcanga, Reto Guler
Summary: Tuberculosis, caused by Mycobacterium tuberculosis, is a significant global health challenge with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. Antisense therapy, utilizing chemically modified antisense oligonucleotides (ASOs), has gained interest as a potential therapeutic approach by targeting disease-causing genes at the mRNA level. Limited but increasing studies are available on the use of ASOs as treatment for infectious diseases.
Article
Pharmacology & Pharmacy
Hiroki Tanaka, Nae Takata, Yu Sakurai, Tokuyuki Yoshida, Takao Inoue, Shinya Tamagawa, Yuta Nakai, Kota Tange, Hiroki Yoshioka, Masatoshi Maeki, Manabu Tokeshi, Hidetaka Akita
Summary: This study investigated the optimal lipid composition of LNPs for the delivery of siRNA and ASO, finding that the optimal compositions for siRNA and ASO were different and differed from those reported for mRNA in previous studies. The key processes for successful delivery of mRNA, siRNA, and ASO were identified as extracellular stability, endosomal escape, and cellular uptake, respectively, indicating the importance of optimizing LNP lipid compositions based on the type of nucleic acids being delivered.
Article
Biochemistry & Molecular Biology
Artur V. Cideciyan, Samuel G. Jacobson, Allen C. Ho, Alexandra V. Garafalo, Alejandro J. Roman, Alexander Sumaroka, Arun K. Krishnan, Malgorzata Swider, Michael R. Schwartz, Aniz Girach
Summary: Treatment of Leber congenital amaurosis due to CEP290 ciliopathy using antisense oligonucleotide (AON) sepofarsen shows significant efficacy, with sustained efficacy observed at 15 months despite a reduction from peak response. The efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and the slow natural rate of CEP290 protein degradation in human fovea cone photoreceptors.
Review
Pharmacology & Pharmacy
Carme Fabrega, Anna Avino, Natalia Navarro, Andreia F. Jorge, Santiago Grijalvo, Ramon Eritja
Summary: In this study, the conjugation of oligonucleotides with lipids and peptides for the development of therapeutics with improved pharmacokinetics is reviewed.
Article
Biochemistry & Molecular Biology
Volodymyr V. V. Oberemok, Oksana A. A. Andreeva, Edie E. E. Alieva
Summary: This paper provides a short review of innovative strategies in the development of antivirals and vaccines against SARS coronaviruses, including antisense antivirals, oligonucleotide adjuvants in vaccines, and oligonucleotide vaccines. Well-developed viral genomic databases create new opportunities for the development of innovative vaccines and antivirals using a post-genomic platform. The most effective vaccines against SARS coronaviruses are those able to form highly effective memory cells for both humoral and cellular immunity. The most effective antivirals need to efficiently stop viral replication without side effects. Oligonucleotide antivirals and vaccines can resist the rapidly changing genomic sequences of SARS coronaviruses using conserved regions of their genomes to generate a long-term immune response. Oligonucleotides have been used as excellent adjuvants for decades, and increasing data show that oligonucleotides could serve as antisense antivirals and antigens in vaccine formulations, becoming a prospective tool for immune system tuning.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Immunology
Rachel V. Jimenez, Alexander J. Szalai
Summary: CRP levels are typically low in healthy individuals, but can rise rapidly in response to tissue damage and inflammation. It is commonly believed that CRP's biological actions are only evident when blood levels are elevated, however studies have shown that even at baseline levels CRP exerts important biological effects.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Mitsuru Naito, Hiroyuki Chaya, Kazuko Toh, Beob Soo Kim, Kotaro Hayashi, Shigeto Fukushima, Tetsuya Nagata, Takanori Yokota, Kazunori Kataoka, Kanjiro Miyata
Summary: The researchers found that chemical modification of oligonucleotides to have higher negative charges facilitated the formation of polyion pairs between the oligonucleotide and bPEG-PLys under harsh biological conditions, leading to enhanced blood circulation of uPICs.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Biochemistry & Molecular Biology
Tetsuhiro Kakimoto, Akira Ogasawara, Kiyoshi Ishikawa, Takashi Kurita, Kumiko Yoshida, Shuichi Harada, Taeko Nonaka, Yoshimi Inoue, Keiko Uchida, Takashi Tateoka, Tetsuya Ohta, Shinji Kumagai, Takashi Sasaki, Hajime Aihara
Summary: In this study, the researchers investigated the therapeutic effect of a novel drug called MT-DUX4-ASO on facioscapulohumeral muscular dystrophy (FSHD). They found that MT-DUX4-ASO can effectively inhibit the expression of the DUX4 gene, improving muscle injury and motor function. The systemic administration of the drug also demonstrated its potential as a promising treatment strategy for FSHD.
Review
Biochemistry & Molecular Biology
Maria Gagliardi, Ana Tari Ashizawa
Summary: ASOs are a novel and promising class of drugs used to selectively inhibit the translation of disease-associated genes. Challenges in ASO delivery and stability require strategic approaches to overcome these limitations for their full potential in precision medicine.
Review
Biochemistry & Molecular Biology
Franciscus C. Vermeer, Jeroen Bremer, Robert J. Sietsma, Aileen Sandilands, Robyn P. Hickerson, Marieke C. Bolling, Anna M. G. Pasmooij, Henny H. Lemmink, Morris A. Swertz, Nine V. A. M. Knoers, K. Joeri van der Velde, Peter C. van den Akker
Summary: Epidermolysis bullosa is a genetic skin condition characterized by skin fragility caused by gene variants, with treatment currently focused on symptom relief. Exon skipping shows potential as a therapeutic strategy for EB, with the severity of the disease linked to gene involvement and variants.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Kathleen M. Schoch, Lubov A. Ezerskiy, Michaela M. Morhaus, Riley N. Bannon, Andrew D. Sauerbeck, Mark Shabsovich, Paymaan Jafar-nejad, Frank Rigo, Timothy M. Miller
Summary: The study found that transient reduction of Trem2 messenger RNA levels in APP/PS1 mice significantly reduced plaque deposition and attenuated microglial association around plaques. The results suggest that Trem2 reduction may activate microglia and aid in plaque removal.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Editorial Material
Transplantation
Sarah Y. A. Ng, Richard Haynes, William G. Herrington
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2020)
Article
Endocrinology & Metabolism
Pengfei Zhu, Sarah Lewington, Richard Haynes, Jonathan Emberson, Martin J. Landray, David Cherney, Mark Woodward, Colin Baigent, William G. Herrington, Natalie Staplin
INTERNATIONAL JOURNAL OF OBESITY
(2020)
Editorial Material
Urology & Nephrology
Matthew P. M. Graham-Brown, William G. Herrington, James O. Burton
Summary: Research suggests that cycling during dialysis may reduce evidence of demand ischaemia, and rehabilitation programs including intradialytic exercise may be more practical for patients on hemodialysis.
CLINICAL KIDNEY JOURNAL
(2021)
Article
Public, Environmental & Occupational Health
Blake Thomson, Roberto Tapia-Conyer, Ben Lacey, Sarah Lewington, Raul Ramirez-Reyes, Diego Aguilar-Ramirez, Louisa Gnatiuc, William G. Herrington, Jason Torres, Eirini Trichia, Rachel Wade, Rory Collins, Richard Peto, Pablo Kuri-Morales, Jesus Alegre-Diaz, Jonathan R. Emberson
Summary: Research in Mexico showed that low-intensity daily smoking is associated with increased mortality risks. Those smoking less than 10 cigarettes per day had a higher mortality rate, but quitting smoking substantially reduced this risk.
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Louisa Gnatiuc, Roberto Tapia-Conyer, Rachel Wade, Raul Ramirez-Reyes, Diego Aguilar-Ramirez, William Herrington, Michael Hill, Sarah Lewington, Jason Torres, Eirini Trichia, Rory Collins, Richard Peto, Robert Clarke, Pablo Kuri-Morales, Jonathan R. Emberson, Jesus Alegre-Diaz
Summary: In this study of Mexican adults, abdominal adiposity (especially the waist-height ratio) was strongly and positively associated with vascular-metabolic mortality, while higher hip circumference was associated with lower vascular-metabolic mortality for a given amount of general and abdominal adiposity.
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2022)
Article
Endocrinology & Metabolism
Diego Aguilar-Ramirez, Jesus Alegre-Diaz, William G. Herrington, Natalie Staplin, Raul Ramirez-Reyes, Louisa Gnatiuc, Michael Hill, Frederik Romer, Jason Torres, Eirini Trichia, Rachel Wade, Rory Collins, Jonathan R. Emberson, Pablo Kuri-Morales, Roberto Tapia-Conyer
Summary: Diabetes and CKD are associated with dyslipidemia and metabolic abnormalities, which lead to atherosclerotic risk. NMR spectroscopy analysis revealed that low kidney function is linked to alterations in lipidic and metabolic profiles in both diabetic and non-diabetic individuals.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
Article
Transplantation
William G. Herrington, Christoph Wanner, Jennifer B. Green, Sibylle J. Hauske, Parminder Judge, Kaitlin J. Mayne, Sarah Y. A. Ng, Emily Sammons, Doreen Zhu, Natalie Staplin, David Preiss, Will Stevens, Karl Wallendszus, Rejive Dayanandan, Carol Knott, Michael Hill, Jonathan Emberson, Susanne Brenner, Vladimir Cejka, Alfred K. Cheung, Zhihong Liu, Jing Li, Peiling Chen, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo Pietro Maggioni, Shinya Goto, Aiko Tomita, Rajat Deo, Katherine Tuttle, Jens Eilbracht, Stefan Hantel, Mark Hopley, Martin J. Landray, Colin Baigent, Richard Haynes
Summary: The EMPA-KIDNEY trial aims to evaluate the effects of empagliflozin on the risk of kidney disease progression or cardiovascular death in patients with chronic kidney disease. The trial includes a widely generalizable population of CKD patients and uses a streamlined design with minimal data collection. Results are anticipated in 2022.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2022)
Letter
Public, Environmental & Occupational Health
Jesus Alegre-Diaz, Louisa G. Friedrichs, Raul Ramirez-Reyes, Rachel Wade, Fiona Bragg, William G. Herrington, Robert Clarke, Richard Peto, Rory Collins, Pablo Kuri-Morales, Jonathan R. Emberson, Roberto Tapia-Conyer
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
(2022)
Article
Peripheral Vascular Disease
Natalie Staplin, William G. Herrington, Federico Murgia, Maysson Ibrahim, Katherine R. Bull, Parminder K. Judge, Sarah Y. A. Ng, Michael Turner, Doreen Zhu, Jonathan Emberson, Martin J. Landray, Colin Baigent, Richard Haynes, Jemma C. Hopewell
Summary: The study findings provide genetic evidence supporting the causal relationship between blood pressure differences and decreased kidney function, glomerular hyperfiltration, and albuminuria. This conclusion is important for understanding the association between blood pressure and kidney diseases.
Article
Transplantation
Kaitlin J. Mayne, Jennifer S. Lees, William G. Herrington
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Cardiac & Cardiovascular Systems
Helena Bleken Ostergaard, Steven H. J. Hageman, Stephanie H. Read, Owen Taylor, Lisa Pennells, Stephen Kaptoge, Carmen Petitjean, Zhe Xu, Fanchao Shi, John William McEvoy, William Herrington, Frank L. J. Visseren, Angela Wood, Bjorn Eliasson, Naveed Sattar, Sarah Wild, Emanuele Di Angelantonio, Jannick A. N. Dorresteijn
Summary: This study aimed to update and calibrate the DIAbetes Lifetime perspective model (DIAL model) using contemporary and representative registry data. The DIAL2 model was derived from the Swedish National Diabetes Register and validated using data from the Scottish Care Information-Diabetes and Clinical Practice Research Datalink. The results showed that the recalibrated DIAL2 model provides an accurate prediction of cardiovascular disease risk in individuals with Type 2 diabetes.
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Louisa Gnatiuc Friedrichs, Rachel Wade, Jesus Alegre-Diaz, Raul Ramirez-Reyes, Adrian Garcilazo-Avila, Carlos Gonzales-Carballo, Rogelio Santacruz-Benitez, Erwin Chiquete, William Herrington, Rory Collins, Richard Peto, Robert Clarke, Jaime Berumen, Jonathan R. Emberson, Pablo Kuri-Morales, Roberto Tapia-Conyer
Summary: This study investigated the association between fat mass index (FMI) and lean mass index (LMI) with vascular-metabolic mortality in Mexican adults. The results showed that higher FMI and LMI were associated with higher risks of vascular-metabolic mortality in both sexes. However, the association between FMI and mortality was stronger in women than in men, while higher LMI was inversely associated with vascular-metabolic mortality, especially in women.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2023)
Editorial Material
Transplantation
Parminder K. Judge, William G. Herrington, Richard Haynes
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Endocrinology & Metabolism
Fiona Bragg, Pablo Kuri-Morales, Jaime Berumen, Adrian Garcilazo-Avila, Carlos Gonzales-Carballo, Raul Ramirez-Reyes, Rogelio Santacruz-Benitez, Diego Aguilar-Ramirez, Louisa Gnatiuc Friedrichs, William G. Herrington, Michael Hill, Eirini Trichia, Rachel Wade, Rory Collins, Richard Peto, Jonathan R. Emberson, Jesus Alegre-Diaz, Roberto Tapia-Conyer
Summary: This study aimed to assess the association between diabetes and the risk of death from infection in Mexico. The results showed a strong link between diabetes and death from infection, particularly in cases of urinary tract infections, skin, bone and connective tissue infections, and septicemia. Furthermore, longer duration of diabetes and higher HbA1c levels were independently associated with an increased risk of death from infection.
BMJ OPEN DIABETES RESEARCH & CARE
(2023)
Article
Urology & Nephrology
Pengfei Zhu, William G. Herrington, Richard Haynes, Jonathan Emberson, Martin J. Landray, Cathie L. M. Sudlow, Mark Woodward, Colin Baigent, Sarah Lewington, Natalie Staplin
Summary: This study utilized data from UK Biobank participants to investigate the relationship between waist-to-hip ratio, BMI, and CKD prevalence. Genetic analyses suggested that mediators such as diabetes and blood pressure play a significant role in the association between central and general adiposity and CKD risk.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2021)