Article
Genetics & Heredity
Jes-Niels Boeckel, Maximilian Moebius-Winkler, Marion Mueller, Sabine Rebs, Nicole Eger, Laura Schoppe, Rewati Tappu, Karoline E. Kokot, Jasmin M. Kneuer, Susanne Gaul, Diana M. Bordalo, Alan Lai, Jan Haas, Mahsa Ghanbari, Philipp Drewe-Boss, Martin Liss, Hugo A. Katus, Uwe Ohler, Michael Gotthardt, Ulrich Laufs, Katrin Streckfuss-Boemeke, Benjamin Meder
Summary: Alternative mRNA splicing is a fundamental process in increasing the versatility of the genome. In this study, SLM2 is identified as a novel cardiac splicing regulator that plays an essential role in maintaining cardiomyocyte integrity.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2022)
Review
Cardiac & Cardiovascular Systems
Celine F. Santiago, Inken G. Huttner, Diane Fatkin
Summary: Dilated cardiomyopathy (DCM) is characterized by heart muscle disorder, with truncating variants in the TTN gene being a common genetic cause. Zebrafish models have emerged as a powerful tool for studying titin function in heart health and disease, providing new insights into mechanisms and potential treatments for DCM.
JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
(2021)
Article
Cardiac & Cardiovascular Systems
Jia Li, Kaiying Wang, Yuchen Zhang, Tuan Qi, Juanjuan Yuan, Lei Zhang, Han Qiu, Jinxi Wang, Huang-Tian Yang, Yi Dai, Yan Song, Xing Chang
Summary: The study analyzed a novel murine model of DMD and examined the feasibility of using a cytidine base editor for exon skipping in vivo. The results showed that AAV9-eTAM treatment in the mouse model restored dystrophin and improved cardiac and skeletal muscle functions significantly.
Article
Multidisciplinary Sciences
Young Jin Kim, Nicole Sivetz, Jessica Layne, Dillon M. Voss, Lucia Yang, Qian Zhang, Adrian R. Krainer
Summary: Mutations in the CFTR gene cause cystic fibrosis (CF), and the CFTR-W1282X mutation results in severe CF. Current therapies for CF benefit most patients, but targeted therapy for patients with the W1282X mutation is lacking. This study explores a potential solution by using an exon-skipping antisense oligonucleotide strategy to bypass nonsense-mediated mRNA decay (NMD) and increase the expression of CFTR protein. The results pave the way for developing allele-specific therapy for CF caused by the W1282X mutation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Ignacio Rodriguez-Polo, Ruediger Behr
Summary: This study proposes the use of myoediting approaches to treat DCM and identifies potential target locations for therapeutic deletion in the Titin gene. It aims to contribute to the development of new therapies for titinopathies and other diseases caused by gene mutations encoding proteins with modular structures.
Article
Health Care Sciences & Services
Maria Livia Iovanescu, Diana Ruxandra Hadareanu, Sebastian Militaru, Cristina Florescu, Constantin Militaru, Ionut Donoiu
Summary: Cardiomyopathies are myocardial disorders that are not caused by specific conditions such as coronary artery disease or congenital heart diseases. They are categorized into specific phenotypes and sub-classified into familial and non-familial forms, with the dilated phenotype being the most common. However, there are overlapping features between these phenotypes, making diagnosis and management challenging. We present a case of three related patients with different types of cardiomyopathies, highlighting the importance of a multimodal approach to diagnosis.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Andreas Brodehl, Carsten Hain, Franziska Flottmann, Sandra Ratnavadivel, Anna Gaertner, Baerbel Klauke, Joern Kalinowski, Hermann Koerperich, Jan Gummert, Lech Paluszkiewicz, Marcus-Andre Deutsch, Hendrik Milting
Summary: Our study identified a pathogenic mutation DES-c.735G > C associated with restrictive cardiomyopathy and atrial fibrillation, causing a splicing defect leading to exon-3 skipping of the DES gene. Further research is needed to explore the genetic implications of this finding in similar cases.
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
Medicine, Research & Experimental
Andre Leier, Marc Moore, Hui Liu, Michael Daniel, Alexis M. Hyde, Ludwine Messiaen, Bruce R. Korf, Jamuna Selvakumaran, Lukasz Ciszewski, Laura Lambert, Jeremy Foote, Margaret R. Wallace, Robert A. Kesterson, George Dickson, Linda Popplewell, Deeann Wallis
Summary: In this study, we investigated the feasibility of using an exon-skipping approach as a genotype-dependent therapy for neurofibromatosis type 1 (NF1). We identified that skipping exons 17 or 52 would minimally affect the function of neurofibromin protein, which was validated through in vitro assessments. Additionally, we demonstrated that antisense phosphorodiamidate morpholino oligomers (PMOs) could restore functional neurofibromin expression in human cell lines with pathogenic variants in exon 17. In a mouse model, homozygous deletion of exon 17 did not affect mouse viability but resulted in altered nesting behavior and systemic lymphoid hyperplasia. These findings suggest that exon skipping should be further investigated as a potential therapeutic approach for NF1 patients with pathogenic variants in exon 17.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Cell Biology
Takahiko Nishiyama, Yu Zhang, Miao Cui, Hui Li, Efrain Sanchez-Ortiz, John R. McAnally, Wei Tan, Jiwoong Kim, Kenian Chen, Lin Xu, Rhonda Bassel-Duby, Eric N. Olson
Summary: Mutations in the RBM20 gene are a common cause of familial dilated cardiomyopathy. The study uses gene editing techniques to correct these mutations and demonstrates that correction can restore normal gene splicing and nuclear localization, while eliminating abnormal ribonucleoprotein granule formation. The effectiveness of this therapy is also validated in a mouse model.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Review
Cardiac & Cardiovascular Systems
Celine F. Santiago, Inken G. Huttner, Diane Fatkin
Summary: The functional consequences of TTNtv and their effects on dilated cardiomyopathy (DCM) have been a subject of debate. Recent evidence indicates that both haploinsufficiency and dominant negative effects are involved in TTNtv-related DCM, leading to reduced titin content and the incorporation of truncated titin into protein aggregates. The extent to which the location of TTNtv affects aggregate formation and protein quality control defects, and contributes to contractile dysfunction, remains unresolved.
CURRENT CARDIOLOGY REPORTS
(2022)
Article
Cardiac & Cardiovascular Systems
Petr G. Vikhorev, Natalia N. Vikhoreva, WaiChun Yeung, Amy Li, Sean Lal, Cristobal G. dos Remedios, Cheavar A. Blair, Maya Guglin, Kenneth S. Campbell, Magdi H. Yacoub, Pieter de Tombe, Steven B. Marston
Summary: This study investigates the effects of truncating mutations in the titin gene (TTN) on the function and characteristics of myofibrils. The researchers found that these mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. They also observed decreased phosphorylation levels of TnI and MyBP-C in DCM patients with TTN-truncating variants.
CARDIOVASCULAR RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Kelly M. Martinovich, Anthony Kicic, Stephen M. Stick, Russell D. Johnsen, Sue Fletcher, Steve D. Wilton
Summary: This study aimed to assess the impact of Cftr exon 9 deletion on the mouse CF phenotype. The results showed that Cftr exon 9 deletion in mice led to intestinal obstructions and a decrease in survival rate. Histological examination revealed increased goblet cells and mucus accumulation in the small intestine of Cftr exon 9 deleted mice. Airway epithelial cell cultures from these mice were unresponsive to forskolin stimulation.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Cody A. Desjardins, Monica Yao, John Hall, Emma O'Donnell, Reshmii Venkatesan, Sean Spring, Aiyun Wen, Nelson Hsia, Peiyi Shen, Ryan Russo, Bo Lan, Tyler Picariello, Kim Tang, Timothy Weeden, Stefano Zanotti, Romesh Subramanian, Oxana Ibraghimov-Beskrovnaya
Summary: The study developed a platform called FORCE that enhances the delivery of phosphorodiamidate morpholino oligomers (PMO) in muscles, enabling exon skipping and dystrophin restoration in patients with muscular dystrophy. FORCE treatment improved functional outcomes compared to unconjugated drugs.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Emanuele Micaglio, Michelle M. Monasky, Andrea Bernardini, Valerio Mecarocci, Valeria Borrelli, Giuseppe Ciconte, Emanuela T. Locati, Marco Piccoli, Andrea Ghiroldi, Luigi Anastasia, Carlo Pappone
Summary: Truncating titin variants in the A-band region of the sarcomere are the most common cause of DCM and have been rarely reported in asymptomatic individuals. Further studies are needed to better understand the clinical significance of novel truncating variants.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, General & Internal
Lauren C. Testa, Yvon Jule, Linnea Lundh, Karine Bertotti, Melissa A. Merideth, Kevin J. O'Brien, Steven D. Nathan, Drew C. Venuto, Souheil El-Chemaly, May Christine V. Malicdan, Bernadette R. Gochuico
Summary: Automated computerized imaging analysis has been shown to provide accurate and reader-independent quantification of pulmonary fibrosis in human histopathology samples. Fibrosis, collagen content, and immune-stained cells can be automatically and individually quantified from serial sections, enhancing the tools available for studying fibrotic lung disease. This analysis method allows for continuous measurement of fibrosis in lung tissue, with potential applications for both research and clinical diagnosis.
FRONTIERS IN MEDICINE
(2021)
Review
Oncology
Lauren C. Testa, Kiran Musunuru
Summary: Base editing (BE) and prime editing (PE) are potential therapeutic strategies that can precisely, efficiently, permanently, and safely correct patients' pathogenic variants and ameliorate disease sequelae. They offer a promising approach, especially for rare genetic diseases.
Letter
Hematology
Madelynn N. Whittaker, Lauren C. Testa, Aidan Quigley, Ishaan Jindal, Saul V. Cortez-Alvarado, Ping Qu, Yifan Yang, Mohamad-Gabriel Alameh, Kiran Musunuru, Xiao Wang
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Respiratory System
Jewel Imani, Steven P. M. Bodine, Anthony M. Lamattina, Diane D. Ma, Shikshya Shrestha, Dawn M. Maynard, Kevin Bishop, Arinze Nwokeji, May Christine V. Malicdan, Lauren C. Testa, Raman Sood, Benjamin Stump, Ivan O. Rosas, Mark A. Perrella, Robert Handin, Lisa R. Young, Bernadette R. Gochuico, Souheil El-Chemaly
Summary: Hermansky-Pudlak syndrome (HPS) is characterized by improper formation of lysosome-related organelles (LROs). This study demonstrates that lung fibroblasts from HPS-1 patients and HPS-1 silenced normal lung fibroblasts show increased migration capacity, which is driven by elevated levels of Myosin IIB. Inhibition of angiotensin receptor with losartan reduces Myosin IIB levels and impedes HPS lung fibroblast migration.
RESPIRATORY RESEARCH
(2022)
Article
Respiratory System
Shachar Abudi-Sinreich, Steven P. Bodine, Tadafumi Yokoyama, Nathanial J. Tolman, Michal Tyrlik, Lauren C. Testa, Chen G. Han, Heidi M. Dorward, Stephen M. Wincovitch, Yair Anikster, William A. Gahl, Resat Cinar, Bernadette R. Gochuico, May Christine Malicdan
Summary: The study investigated the pulmonary effects of systemic delivery of bleomycin in Hps1(ep/ep) mice to develop a murine model of HPSPF that mimics human pulmonary fibrosis progression. Results showed that systemic delivery induced limited acute inflammation followed by slow, dose-dependent fibrogenesis. This model provides a preclinical tool for studying pulmonary fibrosis mechanisms in HPS and developing therapeutics for HPSPF.
RESPIRATORY RESEARCH
(2022)
Article
Cardiac & Cardiovascular Systems
Andrew B. Harvey, Renelyn A. Woltes, Raymond N. Deepe, Hannah G. Tarolli, Jenna R. Drummond, Allison Trouten, Auva Zandi, Jeremy L. Barth, Rupak Mukherjee, Martin J. Romeo, Silvia G. Vaena, Ge Tao, Robin Muise-Helmericks, Paula S. Ramos, Russell A. Norris, Andy Wessels
Summary: This study highlights the importance of SOX9 in the regulation of epicardial cell invasion and emphasizes the role of EPDCs in regulating atrioventricular valve development and homeostasis. It also reports a novel expression profile of Cd109, a gene with previously unknown relevance in heart development.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Review
Cardiac & Cardiovascular Systems
MariaSanta C. Mangione, Jinhua Wen, Dian J. Cao
Summary: mTOR, a mechanistic target of rapamycin, is an evolutionarily conserved pathway that plays a fundamental role in nutrient sensing, growth, metabolism, lifespan, and aging. Recent studies have highlighted the regulatory role of mTOR in innate immune responses and its involvement in the pathogenesis of cardiovascular diseases, especially in acute inflammation and atherosclerotic cardiovascular disease. This review also discusses mTOR's role in trained immunity, immune senescence, and clonal hematopoiesis, as well as its architecture and regulatory complexes.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Article
Cardiac & Cardiovascular Systems
Junlin Li, Yajun Gong, Yiren Wang, Huihui Huang, Huan Du, Lianying Cheng, Cui Ma, Yongxiang Cai, Hukui Han, Jianhong Tao, Gang Li, Panke Cheng
Summary: Myocardial ischemia-reperfusion injury is closely related to the final infarct size in acute myocardial infarction. Regulatory T cells play an important role in the inflammatory response after AMI, but different subtypes of Tregs have different effects on the injury.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)
Article
Cardiac & Cardiovascular Systems
Yuxin Chu, Yutao Hua, Lihao He, Jin He, Yunxi Chen, Jing Yang, Ismail Mahmoud, Fanfang Zeng, Xiaochang Zeng, Gloria A. Benavides, Victor M. Darley-Usmar, Martin E. Young, Scott W. Ballinger, Sumanth D. Prabhu, Cheng Zhang, Min Xie
Summary: This study demonstrates that administering beta-hydroxybutyrate (beta-OHB) at the time of reperfusion can reduce infarct size and preserve cardiac function by activating autophagy and preserving mitochondrial homeostasis, potentially through mTOR inhibition.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2024)