Article
Pharmacology & Pharmacy
Hamad Ali, Faisal Khan, Syed Ghulam Musharraf
Summary: The study demonstrated that acyclovir induces the expression of the gamma-globin gene and HbF synthesis, without affecting terminal erythroid differentiation and proliferation. It also downregulated gamma-globin repressors BCL11A and SOX6, while upregulating the master erythroid transcription factor GATA-1, suggesting its potential as an effective HbF inducer for treating beta-globin disorders.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cell Biology
Yang Yang, Ren Ren, Lana C. Ly, John R. Horton, Fudong Li, Kate G. R. Quinlan, Merlin Crossley, Yunyu Shi, Xiaodong Cheng
Summary: The study uncovered ZBTB7A/LRF as a key molecular regulator of fetal globin expression, with mutations affecting its DNA binding ability, informing genome-editing strategies for treating hemoglobinopathies.
Article
Genetics & Heredity
Divya S. Vinjamur, Qiuming Yao, Mitchel A. Cole, Connor McGuckin, Chunyan Ren, Jing Zeng, Mir Hossain, Kevin Luk, Scot A. Wolfe, Luca Pinello, Daniel E. Bauer
Summary: The research identified ZNF410 as an indirect repressor of fetal hemoglobin by regulating CHD4 expression, resulting in the silencing of fetal hemoglobin.
Article
Multidisciplinary Sciences
Shohei Takase, Takashi Hiroyama, Fumiyuki Shirai, Yuki Maemoto, Akiko Nakata, Mayumi Arata, Seiji Matsuoka, Takeshi Sonoda, Hideaki Niwa, Shin Sato, Takashi Umehara, Mikako Shirouzu, Yosuke Nishigaya, Tatsunobu Sumiya, Noriaki Hashimoto, Ryosuke Namie, Masaya Usui, Tomokazu Ohishi, Shun-ichi Ohba, Manabu Kawada, Yoshihiro Hayashi, Hironori Harada, Tokio Yamaguchi, Yoichi Shinkai, Yukio Nakamura, Minoru Yoshida, Akihiro Ito
Summary: Sickle cell disease (SCD) is caused by beta-globin gene mutations. G9a inhibitors, including RK-701, have been proposed as therapeutic agents for inducing fetal globin expression. This study describes the development of RK-701 as a selective and non-genotoxic G9a inhibitor, which upregulates BGLT3 long non-coding RNA and induces gamma-globin expression. BGLT3 is identified as an essential factor for gamma-globin induction and its universal role suggests its importance in SCD treatment.
NATURE COMMUNICATIONS
(2023)
Review
Medicine, General & Internal
Siti Nur Nabeela A'ifah Mohammad, Salfarina Iberahim, Wan Suriana Wan Ab Rahman, Mohd Nazri Hassan, Hisham Atan Edinur, Maryam Azlan, Zefarina Zulkafli
Summary: Anemia, characterized by decreased oxygen transport due to low red blood cells or hemoglobin levels, can cause fatigue and weakness in individuals. It can be hereditary or acquired, with strategies like increasing fetal hemoglobin helping to alleviate symptoms.
Review
Pharmacology & Pharmacy
Martin H. Steinberg
Summary: This article examines the pathophysiology of beta hemoglobinopathies, the physiology of HbF, intracellular distribution, and the regulation of HbF expression. Inducing high levels of HbF by targeting its regulatory pathways pharmacologically or with cell-based therapeutics provides major clinical benefit and perhaps a 'cure.'
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)
Article
Genetics & Heredity
Dian Lu, Zhiliang Xu, Zhiyong Peng, Yinghong Yang, Bing Song, Zeyu Xiong, Zhirui Ma, Hongmei Guan, Bangzhu Chen, Yukio Nakamura, Juan Zeng, Nengqing Liu, Xiaofang Sun, Diyu Chen
Summary: This study proposes a novel Cas9/AAV6-mediated genome editing strategy for treating beta-thalassemia. By introducing naturally occurring HPFH mutations and disrupting BCL11A binding sites in HBG1/HBG2 promoters, precise on-target editing and significantly increased gamma-globin expression were observed.
FRONTIERS IN GENETICS
(2022)
Review
Pharmacology & Pharmacy
Rahyssa Rodrigues Sales, Barbara Lisboa Nogueira, Jessica Abdo Goncalves Tosatti, Karina Braga Gomes, Marcelo Rizzatti Luizon
Summary: Hydroxyurea is commonly used for the treatment of sickle cell anemia (SCA), but there is variability in patient response. This systematic review explores the impact of genetic polymorphisms on HbF levels in SCA patients treated with hydroxyurea, and identifies SNPs and genes associated with HbF changes. The findings suggest that changes in HbF levels upon hydroxyurea therapy are likely regulated by multiple loci.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Medicine, General & Internal
Anthony Quagliano, Daniel Acevedo, Patrik Hardigan, Samiksha Prasad
Summary: Beta-hemoglobinopathies, including sickle cell disease and beta-thalassemia, are genetic disorders characterized by mutations in the HBB gene. Current treatments involve pharmacological agents to raise levels of fetal hemoglobin, but gene editing technologies like CRISPR/Cas9 offer potential permanent effects. This meta-analysis compared two gene editing targets, BCL11A and HBG1/2, and found that HBG1/2 significantly increased HbF expression compared to BCL11A.
FRONTIERS IN MEDICINE
(2022)
Review
Chemistry, Medicinal
Rayan Bou-Fakhredin, Lucia De Franceschi, Irene Motta, Maria Domenica Cappellini, Ali T. Taher
Summary: Better understanding of gamma-globin regulation has led to advancements in pharmacologic agents for HbF induction and identification of novel HbF-inducing strategies.
Article
Biochemistry & Molecular Biology
Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Ilaria Lampronti, Monica Borgatti, Chiara Scapoli, Roberto Gambari, Alessia Finotti
Summary: This study analyzed Cinchona alkaloids as natural HbF-inducing agents in human erythroid cells, and found that cinchonidine and quinidine are potent inducers of gamma-globin mRNA and HbF in erythroid progenitor cells isolated from beta-thalassemia patients. These compounds may be considered for the development of pre-clinical approaches for therapeutic protocols of beta-thalassemia.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Lucia Carmela Cosenza, Cristina Zuccato, Matteo Zurlo, Roberto Gambari, Alessia Finotti
Summary: Gene editing is an effective strategy for correcting genetic mutations in monogenic hereditary diseases, and combining it with HbF induction protocols can achieve de novo production of HbA and an increase in induced HbF.
Article
Biotechnology & Applied Microbiology
Yousef Saeed Mohammad Za'ror, Zefarina Zulkafli, Laith Naser Al-Eitan, Lina Elsalem, Belal Abdelaziz Al-Husein, Maryam Azlan
Summary: This study found that the combination therapy of erythropoietin and stem cell factor has no effect on the expression of the β-globin gene, BCL11A, KLF1, and ERK of the MAPK pathway in sickle cell disease.
BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL
(2022)
Article
Hematology
Woratree Kaewsakulthong, Phitchapa Pongpaksupasin, Tiwaporn Nualkaew, Suradej Hongeng, Suthat Fucharoen, Natee Jearawiriyapaisarn, Orapan Sripichai
Summary: The use of LSD1 inhibitor RN-1 significantly increases gamma-globin transcript and HbF expression levels in erythroid cells derived from beta(0)-thalassemia/HbE patients, without affecting cell viability and proliferation at low concentration, but leading to decreased cell numbers at high concentration.
HEMATOLOGY REPORTS
(2021)
Article
Medicine, Research & Experimental
Naoya Uchida, Claire M. Drysdale, Tina Nassehi, Jackson Gamer, Morgan Yapundich, Julia DiNicola, Yoshitaka Shibata, Malikiya Hinds, Bjorg Gudmundsdottir, Juan J. Haro-Mora, Selami Demirci, John F. Tisdale
Summary: The development of a non-integrating lentiviral system encoding Cas9 protein, guide RNA, and donor DNA allows for efficient one-time correction of hereditary diseases, improving prospects for genome editing.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Article
Immunology
George W. Carnell, Claudia M. Trombetta, Francesca Ferrara, Emanuele Montomoli, Nigel J. Temperton
Summary: Influenza B virus significantly contributes to global morbidity, mortality, and economic loss related to influenza. Current gold standard serological assays for influenza B have operational issues with sensitivity and specific antigen requirement. This study compared gold standard assays with a newer Pseudotype-based Microneutralisation assay, finding strong correlations for strains in the Yamagata lineage but not in the Victoria lineage.
Article
Immunology
Francesca Ferrara, Joanne Marie M. Del Rosario, Kelly A. S. da Costa, Rebecca Kinsley, Simon Scott, Sasan Fereidouni, Craig Thompson, Paul Kellam, Sarah Gilbert, George Carnell, Nigel Temperton
Summary: Traditional methods to assess influenza vaccine immunogenicity have limitations, leading researchers to develop innovative approaches using pseudotypes to study antibody responses. These pseudotypes show promise as effective tools in influenza research.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Medicine, Research & Experimental
Scott A. Peslak, Selami Demirci, Vemika Chandra, Byoung Ryu, Saurabh K. Bhardwaj, Jing Jiang, Jeremy W. Rupon, Robert E. Throm, Naoya Uchida, Alexis Leonard, Khaled Essawi, Aylin C. Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Robert E. Donahue, Francesca Ferrara, Matthew Wielgosz, Osheiza Abdulmalik, Nicole Hamagami, Paula Germino-Watnick, Anh Le, Rebecca Chu, Malikiya Hinds, Mitchell J. Weiss, Wei Tong, John F. Tisdale, Gerd A. Blobel
Summary: This study demonstrates that forced enhancer rewiring can alter gene expression and presents a potential strategy for therapeutic purposes. By transducing hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) and forcing contact between the enhancer and the target gene, elevated expression of the target gene was achieved in adult-type erythroid cells. This proof of concept was demonstrated in both mice and rhesus macaque models.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Multidisciplinary Sciences
Koon-Kiu Yan, Jose Condori, Zhijun Ma, Jean-Yves Metais, Bensheng Ju, Liang Ding, Yogesh Dhungana, Lance E. Palmer, Deanna M. Langfitt, Francesca Ferrara, Robert Throm, Hao Shi, Isabel Risch, Sheetal Bhatara, Bridget Shaner, Timothy D. Lockey, Aimee C. Talleur, John Easton, Michael M. Meagher, Jennifer M. Puck, Morton J. Cowan, Sheng Zhou, Ewelina Mamcarz, Stephen Gottschalk, Jiyang Yu
Summary: Lentiviral vector (LV)-based gene therapy shows promise in treating various diseases. By analyzing patient samples, we found LV integrome signatures related to genomics, epigenomics, and the 3D structure of the genome. These signatures were validated in cellular therapies and differences in 3D genome signatures between LV and gamma retrovirus integromes were identified, potentially explaining the lower risk of mutations in LV-based gene therapy.
Article
Cell Biology
Naoya Uchida, Linhong Li, Tina Nassehi, Claire M. Drysdale, Morgan Yapundich, Jackson Gamer, Juan J. Haro-Mora, Selami Demirci, Alexis Leonard, Aylin C. Bonifacino, Allen E. Krouse, N. Seth Linde, Cornell Allen, Madhusudan Peshwa, Suk See De Ravin, Robert E. Donahue, Harry L. Malech, John F. Tisdale
Summary: The study achieved successful gene correction of SCD mutation in CD34+ cells through electroporation and demonstrated engraftment of edited cells in xenograft mice and macaques, providing valuable insights for designing HSC-targeted gene correction trials.
CELL REPORTS MEDICINE
(2021)
