Review
Cardiac & Cardiovascular Systems
Martine Paquette, Sophie Bernard
Summary: Multifactorial chylomicronemia syndrome (MCS) is a common cause of severe hypertriglyceridemia, associated with an increased risk of acute pancreatitis, cardiovascular disease, and non-alcoholic steatohepatitis. The prevalence of MCS is increasing due to the rising rates of obesity, metabolic syndrome, and type 2 diabetes. Differentiating familial chylomicronemia syndrome from MCS is crucial for appropriate treatment. Recent cohort studies have helped to distinguish between these conditions and evidence suggests that MCS itself is heterogeneous. This mini-review summarizes the genetic determinants of metabolic risk and the latest developments in pharmacological and non-pharmacological treatment options for MCS.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Review
Endocrinology & Metabolism
Mrinali Tripathi, April Wong, Victoria Solomon, Hussein N. Yassine
Summary: The study estimated the prevalence of probable FCS in a major Southern California Academic Center and provided a systematic review of past FCS studies and management recommendations. Using the recommended criteria, probable FCS cases can be identified for early diagnosis and management.
ENDOCRINE PRACTICE
(2021)
Article
Cardiac & Cardiovascular Systems
Josivan Gomes Lima, Lucia Helena C. Nobrega, Flora Tamires Moura Bandeira, Andre Gustavo Pires Sousa, Taisa Barreto Medeiros de Araujo Macedo, Ana Claudia Cavalcante Nogueira, Antonio Fernandes de Oliveira Filho, Renato Jorge Alves, Maria Helane Costa Gurgel Castelo, Fabiana Maria Silva Coelho, Rayana Elias Maia, Debora Nobrega Lima, Ana Rafaela de Souza Timoteo, Julliane Tamara Araujo de Melo Campos
Summary: This study described a novel pathogenic intronic mutation in GPIHBP1 in patients from the Northeast region of Brazil, suggesting the occurrence of a founder effect. This mutation is likely to alter GPIHBP1 pre-mRNA processing and affect around 50% of the domain structure.
Article
Biochemistry & Molecular Biology
Franklin Hanna Rodriguez, Jorge Mario Estrada, Henry Mauricio Arenas Quintero, Juan Patricio Nogueira, Gloria Liliana Porras-Hurtado
Summary: This study describes a screening program and its results for severe hypertriglyceridemia in Colombia. Among the 2415 patients screened, only one patient was diagnosed with familial chylomicronemia syndrome. The study suggests that more programs of this nature should be developed in the region, given the increasing importance of early detection of this metabolic disorder.
LIPIDS IN HEALTH AND DISEASE
(2023)
Editorial Material
Pharmacology & Pharmacy
Michele Glodowski, Shannon Christen, David R. Saxon, Robert A. Hegele, Robert H. Eckel
Summary: Chylomicronemia is caused by genetic mutations and variants, with the PPARG gene playing a role in the condition. These variations can increase susceptibility to chylomicronemia and affect triglyceride levels in individuals.
JOURNAL OF CLINICAL LIPIDOLOGY
(2021)
Article
Pharmacology & Pharmacy
Raul D. Santos, Alberto Lorenzatti, Pablo Corral, Juan Patricio Nogueira, Alberto M. Cafferata, Daniel Aimone, Charles M. Lourenco, Maria Cristina Izar, Josivan G. Lima, Ana Maria Lottenberg, Rodrigo Alonso, Karla Garay, Alvaro Ruiz Morales, Hernando Vargas-Uricoechea, Christian A. Colon Pena, Alejandro Roman-Gonzalez
Summary: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by late diagnosis, heterogeneity in disease progression, and increased risk of pancreatitis and secondary diabetes. Molecular diagnosis is uncommon, with loss of function variants on the lipoprotein lipase gene being a common etiology. Low awareness among health professionals contributes to inadequate care for FCS patients.
JOURNAL OF CLINICAL LIPIDOLOGY
(2021)
Review
Peripheral Vascular Disease
Miriam Larouche, Etienne Khoury, Diane Brisson, Daniel Gaudet
Summary: This review focuses on the development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory hypertriglyceridemia to prevent cardiovascular disease or other morbidities.
CURRENT ATHEROSCLEROSIS REPORTS
(2023)
Article
Medicine, General & Internal
Adrienn Tuennemann-Tarr, Hubert Scharnagl, Julius L. Katzmann, Paulina Stuerzebecher, Ulrich Laufs
Summary: Familial chylomicronemia syndrome is a genetic disorder associated with increased risk of acute pancreatitis due to severe hypertriglyceridemia. In this case report, treatment with the apoCIII inhibitor volanesorsen significantly reduced serum triglyceride levels in a patient with this syndrome, demonstrating good tolerability and potential efficacy for managing the condition.
Review
Biochemistry & Molecular Biology
Israa Dib, Alia Khalil, Racha Chouaib, Yolla El-Makhour, Hiba Noureddine
Summary: Cardiovascular diseases have become the world's top killer, with a strong link to elevated triglyceride levels. Apolipoprotein C-III plays a key role in cardiovascular issues, particularly its SstI polymorphism is consistently associated with increased CVD risk.
MOLECULAR BIOLOGY REPORTS
(2021)
Article
Endocrinology & Metabolism
Martine Paquette, Julie Amyot, Manon Fantino, Alexis Baass, Sophie Bernard
Summary: This study compared the clinical and biochemical characteristics of patients with familial chylomicronemia syndrome (FCS), positive multifactorial chylomicronemia syndrome (MCS), and negative-MCS. It was found that the prevalence of pancreatitis differed significantly among the groups, with rare variants being one of the predictors of pancreatitis in MCS patients.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
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
Endocrinology & Metabolism
Martine Paquette, Julie Amyot, Manon Fantino, Alexis Baass, Sophie Bernard
Summary: This study compared the clinical and biochemical characteristics of individuals with familial chylomicronemia syndrome (FCS), positive multifactorial chylomicronemia syndrome (MCS), and negative MCS. It was found that MCS individuals carrying a rare variant exhibited an intermediate phenotype between FCS and negative MCS subjects. Identification of higher-risk MCS patients for additional treatment is essential.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
Article
Pharmacology & Pharmacy
Ewa Karwatowska-Prokopczuk, Jean-Claude Tardif, Daniel Gaudet, Christie M. Ballantyne, Michael D. Shapiro, Patrick M. Moriarty, Seth J. Baum, Eric St Amour, Veronica J. Alexander, Shuting Xia, James D. Otvos, Joseph L. Witztum, Sotirios Tsimikas
Summary: Olezarsen treatment improves lipoprotein concentration and particle size by reducing TRLs, remodeling to larger LDL particles, and increasing small HDL subspecies.
JOURNAL OF CLINICAL LIPIDOLOGY
(2022)
Article
Pharmacology & Pharmacy
Jose Rioja, Maria Jose Ariza, Maria Jose Benitez-Toledo, Javier Espildora-Hernandez, Inmaculada Coca-Prieto, Teresa Arrobas-Velilla, Ana Camacho, Gunilla Olivecrona, Miguel Angel Sanchez-Chaparro, Pedro Valdivielso
Summary: This study aimed to establish and validate cut-off points for the diagnosis of familial chylomicronemia syndrome (FCS) based on the ROC curve. The results showed that all FCS patients had post-heparin plasma lipoprotein lipase (LPL) activity below 25.1 mU/mL, with no overlap between FCS and multifactorial chylomicronemia syndrome (MCS) groups. Therefore, in addition to genetic testing, LPL activity in subjects with severe hypertriglyceridemia can serve as a reliable criterion for FCS diagnosis with a cut-off of 25.1 mU/mL.
JOURNAL OF CLINICAL LIPIDOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Florian Schlotter, Renata C. C. de Freitas, Maximillian A. Rogers, Mark C. Blaser, Pin-Jou Wu, Hideyuki Higashi, Arda Halu, Farwah Iqbal, Allison B. Andraski, Cayla N. Rodia, Shiori Kuraoka, Jennifer R. Wen, Michael Creager, Tan Pham, Joshua D. Hutcheson, Simon C. Body, Alison B. Kohan, Frank M. Sacks, Masanori Aikawa, Sasha A. Singh, Elena Aikawa
Summary: This study investigates the role of apolipoproteins in calcific aortic valve disease (CAVD). Specific apolipoproteins were found to be associated with valvular calcification, with apoC-III identified as an active and modifiable driver of CAVD.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Endocrinology & Metabolism
Erin S. Morgan, Li-Jung Tai, Nguyen C. Pham, Julia K. Overman, Lynnetta M. Watts, Anne Smith, Shiangtung W. Jung, Martin Gajdosik, Martin Krssak, Michael Krebs, Richard S. Geary, Brenda F. Baker, Sanjay Bhanot
Article
Biochemistry & Molecular Biology
Jason D. Ferrone, Gourab Bhattacharjee, Alexey S. Revenko, Thomas A. Zanardi, Marshelle S. Warren, Frederick J. Derosier, Nicholas J. Viney, Nguyen C. Pham, Gwendolyn E. Kaeser, Brenda F. Baker, Eugene Schneider, Steven G. Hughes, Brett P. Monia, A. Robert MacLeod
NUCLEIC ACID THERAPEUTICS
(2019)
Article
Pharmacology & Pharmacy
Stanley T. Crooke, Xue-hai Liang, Rosanne M. Crooke, Brenda F. Baker, Richard S. Geary
Summary: This article discusses the application and comparison of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) in a pharmacological context. While the two approaches share common features, they also have significant differences in terms of chemical modifications, mechanisms of action, and pharmacokinetic properties.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Clinical Neurology
P. James B. Dyck, Teresa Coelho, Marcia Waddington Cruz, Thomas H. Brannagan, Sami Khella, Chafic Karam, John L. Berk, Michael J. Polydefkis, John C. Kincaid, Janice F. Wiesman, William J. Litchy, Michelle L. Mauermann, Elizabeth J. Ackermann, Brenda F. Baker, Shiangtung W. Jung, Spencer Guthrie, Michael Pollock, Peter J. Dyck
Article
Clinical Neurology
P. James B. Dyck, John C. Kincaid, Janice F. Wiesman, Michael Polydefkis, William J. Litchy, Michelle L. Mauermann, Elizabeth J. Ackermann, Spencer Guthrie, Michael Pollock, Shiangtung W. Jung, Brenda F. Baker, Peter J. Dyck
Article
Gastroenterology & Hepatology
Rohit Loomba, Erin Morgan, Lynnetta Watts, Shuting Xia, Lisa A. Hannan, Richard S. Geary, Brenda F. Baker, Sanjay Bhanot
LANCET GASTROENTEROLOGY & HEPATOLOGY
(2020)
Article
Medicine, General & Internal
Danny M. Cohn, Nicholas J. Viney, Laure M. Fijen, Eugene Schneider, Veronica J. Alexander, Shuting Xia, Gwendolyn E. Kaeser, Charvi Nanavati, Brenda F. Baker, Richard S. Geary, Marcel Levi, Joost C. M. Meijers, Erik S. G. Stroes
NEW ENGLAND JOURNAL OF MEDICINE
(2020)
Article
Cardiac & Cardiovascular Systems
Nicholas J. Viney, Shuling Guo, Li-Jung Tai, Brenda F. Baker, Mariam Aghajan, Shiangtung W. Jung, Rosie Z. Yu, Sheri Booten, Heather Murray, Todd Machemer, Sebastien Burel, Sue Murray, Gustavo Buchele, Sotirios Tsimikas, Eugene Schneider, Richard S. Geary, Merrill D. Benson, Brett P. Monia
Summary: AKCEA-TTR-L-Rx, a ligand-conjugated antisense drug, showed significantly increased potency compared to unconjugated inotersen in human hepatocyte cell culture and transgenic hTTR mice expressing a mutated human genomic TTR sequence. In a phase 1 study with healthy volunteers, AKCEA-TTR-L-Rx demonstrated a reduction in TTR levels and a favorable safety profile, supporting its further development for the treatment of ATTR polyneuropathy and cardiomyopathy.
Review
Biochemistry & Molecular Biology
Stanley T. Crooke, Xue-Hai Liang, Brenda F. Baker, Rosanne M. Crooke
Summary: Antisense technology has shown promise in delivering RNA-targeted drugs, with several approved for commercial use. Ongoing research is exploring the effects and molecular mechanisms of various ASOs in different diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Biotechnology & Applied Microbiology
Stanley T. Crooke, Brenda F. Baker, Rosanne M. Crooke, Xue-hai Liang
Summary: Antisense technology is delivering on its promise to treat diseases by targeting RNA, with nine single-stranded ASO drugs approved for commercial use. In addition to rare diseases, ASOs in development are intended to treat common diseases and show potential for increased potency and performance.
NATURE REVIEWS DRUG DISCOVERY
(2021)
Article
Biochemistry & Molecular Biology
Wesley Partridge, Shuting Xia, T. Jesse Kwoh, Sanjay Bhanot, Richard S. Geary, Brenda F. Baker
Summary: The study demonstrated that compared to mipomersen, newer 2'MOE ASOs showed improved tolerability profiles, with a significant reduction in the incidence of flu-like reactions.
NUCLEIC ACID THERAPEUTICS
(2021)
Article
Medicine, General & Internal
Laure M. Fijen, Marc A. Riedl, Laura Bordone, Jonathan A. Bernstein, Jason Raasch, Raffi Tachdjian, Timothy Craig, William R. Lumry, Michael E. Manning, Veronica J. Alexander, Kenneth B. Newman, Alexey Revenko, Brenda F. Baker, Charvi Nanavati, A. Robert MacLeod, Eugene Schneider, Danny M. Cohn
Summary: In this small phase 2 trial, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo among patients with hereditary angioedema. The change in quality of life score was more significant in the donidalorsen group, with a relatively lower incidence of adverse events.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Sebastien A. Burel, Todd Machemer, Brenda F. Baker, T. Jesse Kwoh, Suzanne Paz, Husam Younis, Scott P. Henry
Summary: A PBMC-based assay was developed to identify ASOs that can activate a cellular innate immune response beyond an acceptable level. The development of this assay was initiated when unexpected increases in IL-6 and CRP were observed in healthy human volunteers during a phase I clinical trial of ISIS 353512. The study found that the IL-6 increase was caused by B cell activation and mediated by TLR9. By using different PBMC donors, the assay could reliably assess the immune potential of ASOs.
NUCLEIC ACID THERAPEUTICS
(2022)
Review
Clinical Neurology
Thomas H. Brannagan, John L. Berk, Julian D. Gillmore, Mathew S. Maurer, Marcia Waddington-Cruz, Marianna Fontana, Ahmad Masri, Laura Obici, Michela Brambatti, Brenda F. Baker, Lisa A. Hannan, Gustavo Buchele, Nick J. Viney, Teresa Coelho, Jose Nativi-Nicolau
Summary: Transthyretin-mediated amyloidosis is a rare and fatal disease characterized by the aggregation and deposition of amyloid transthyretin fibrils in multiple organs and tissues. One strategy to treat this disease is to reduce the production of transthyretin by targeting its mRNA or gene. This review focuses on the use of gene silencing tools to reduce transthyretin production and discusses strategies for targeted delivery to hepatocytes, where transthyretin is predominantly expressed.
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Article
Biochemistry & Molecular Biology
Brenda F. F. Baker, Shuting Xia, Wesley Partridge, T. Jesse Kwoh, Sotirios Tsimikas, Sanjay Bhanot, Richard S. S. Geary
Summary: Receptor-mediated delivery of GalNAc(3)-conjugated antisense oligonucleotides (ASOs) has shown increased efficacy compared to unconjugated forms for RNA targets expressed by hepatocytes. In this study, a comprehensive safety assessment of GalNAc(3)-conjugated 2 ' MOE-modified ASOs was conducted based on data from phase 2 studies involving 642 participants. The results demonstrated good tolerability of the GalNAc(3)-conjugated ASOs with no observed class effect compared to placebo, supporting previous findings from phase 1 studies.
NUCLEIC ACID THERAPEUTICS
(2023)
