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EMBO Molecular Medicine

All articles accepted from 14 August 2012 are published under the terms of the Creative Commons Attribution License.   Articles accepted before this date were published under the agreement as stated in the final article.

Cover image for Vol. 6 Issue 12

Edited By: Stefanie Dimmeler (Chief Editor), Roberto Buccione and Céline Carret (EMBO Editors)

Online ISSN: 1757-4684

Virtual Issue: Genetic diseases and gene therapy

This virtual issue collects great EMBO Molecular Medicine articles covering exciting developments in genetic diseases and gene replacement therapy and featuring insights into pathophysiology, therapy and new methods. Enjoy!

 


Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation
Yongbo Wang, Andreas Gogol-Döring, Hao Hu, Sebastian Fröhler, Yunxia Ma, Marvin Jens, Jonas Maaskola, Yasuhiro Murakawa, Claudia Quedenau, Markus Landthaler, Vera Kalscheuer, Dagmar Wieczorek, Yang Wang, Yuhui Hu and Wei Chen
EMBO Mol Med 2013, 5(9), 1431–1442

EMBO Molecular Medicine - Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation

This study establishes RBM10 as an important regulator of alternative splicing and explains the splicing defects in TARP syndrome patients with in-frame RBM10 deletions.


Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice
Christina Gedicke-Hornung, Verena Behrens-Gawlik, Silke Reischmann, Birgit Geertz, Doreen Stimpel, Florian Weinberger, Saskia Schlossarek, Guillaume Précigout, Ingke Braren, Thomas Eschenhagen, Giulia Mearini, Stéphanie Lorain, Thomas Voit, Patrick A. Dreyfus, Luis Garcia and Lucie Carrier
EMBO Mol Med 2013, 5(7), 1128–1145

EMBO Molecular Medicine - Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice

Exon skipping is a promising therapy for selected genetic diseases. Here, the authors show as a proof-of-principle that MYBPC3 mutation-induced cardiomyopathy can be rescued by AAV-U7-antisense oligoribonucleotides in the heart of neonatal mice.


Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds
Jonathan J. Cherry, Erkan Y. Osman, Matthew C. Evans, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny, Marcie A. Glicksman, Christian L. Lorson and Elliot J. Androphy
EMBO Mol Med 2013, 5(7), 1103–1118

EMBO Molecular Medicine - Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

Spinal muscular atrophy (SMA) is caused by loss of SMN and is one of the leading heritable causes of infant death. The Authors describe new small molecules that increase SMN levels leading to improved lifespan and motor function in a SMA mouse model.


A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA
Nicolina Cristina Sorrentino, Luca D'Orsi, Irene Sambri, Edoardo Nusco, Ciro Monaco, Carmine Spampanato, Elena Polishchuk, Paola Saccone, Elvira De Leonibus, Andrea Ballabio and Alessandro Fraldi
EMBO Mol Med 2013, 5(5), 675-690

EMBO Molecular Medicine - A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA

Gene transfer of a liver-targeted sulfamidase engineered for increased secretion and blood brain barrier permeability, effectively ameliorates overall brain pathology and behavioural phenotype in treated Mucopolysaccharidosis (MPS) type IIIA mice.


Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice
Chiara Mozzetta, Silvia Consalvi, Valentina Saccone, Matthew Tierney, Adamo Diamantini, Kathryn J. Mitchell, Giovanna Marazzi, Giovanna Borsellino, Luca Battistini, David Sassoon, Alessandra Sacco and Pier Lorenzo Puri
EMBO Mol Med 2013, 5(4), 626-639

EMBO Molecular Medicine - Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice

The Authors describe the biological basis of pharmacological correction by HDAC inhibitors of a key event in Duchenne Muscular Dystrophy, the exhaustion of muscle satellite cell regeneration potential and parallel fibroadipogenic degeneration.


Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency
Nunzia Pastore, Keith Blomenkamp, Fabio Annunziata, Pasquale Piccolo, Pratibha Mithbaokar, Rosa Maria Sepe, Francesco Vetrini, Donna Palmer, Philip Ng, Elena Polishchuk, Simona Iacobacci, Roman Polishchuk, Jeffrey Teckman, Andrea Ballabio and Nicola Brunetti-Pierri
EMBO Mol Med 2013, 5(3), 397-412

EMBO Molecular Medicine - Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency

The authors show that transcription factor EB (TFEB) gene transfer corrects liver disease in alpha-1-antitrypsin deficiency, underlying the potential to extend this novel strategy to other human disorders.


The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes
Alessia Indrieri, Ivan Conte, Giancarlo Chesi, Alessia Romano, Jade Quartararo, Rosarita Tatè, Daniele Ghezzi, Massimo Zeviani, Paola Goffrini, Ileana Ferrero, Paola Bovolenta and Brunella Franco
EMBO Mol Med 2013, 5(2), 280-293

EMBO Molecular Medicine - The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes

The X-linked disorder microphtalmia with skin lesions (MLS) is caused by HCCS gene mutations. The disease phenotype is now be explained by the increased non-conventional caspase-9 -mediated cell death in the brain and eyes due to HCCS impairment.


Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer
Bruno Bernardes de Jesus, Elsa Vera, Kerstin Schneeberger, Agueda M. Tejera, Eduard Ayuso, Fatima Bosch and Maria A. Blasco
EMBO Mol Med 2012, 4(8), 691-704

EMBO Molecular Medicine - Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

The Authors have shown for the first time that mice that received a single treatment with telomerase, an enzyme that helps maintain the physical integrity of the ends of chromosomes, showed drastic improvements in health, fitness and longevity without increasing the risk of cancer development.

Accompanying Closeup
Telomerase gene therapy: a novel approach to combat aging
Virginia Boccardi and Utz Herbig
EMBO Mol Med 2012, 4(8), 685-687


Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell
Luca Biasco, Alessandro Ambrosi, Danilo Pellin, Cynthia Bartholomae, Immacolata Brigida, Maria Grazia Roncarolo, Clelia Di Serio, Christof von Kalle, Manfred Schmidt, Alessandro Aiuti
EMBO Mol Med 2011, 3(2), 89-101

EMBO Molecular Medicine - Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell

Retroviral vectors have been used as effective tools to transfer therapeutic genes for the treatment of haematological inherited disorders. Here, the authors study the properties of genomic integration sites of a gammaretroviral vector in haematopoietic cells from GT-treated patients affected by ADA-SCID, treated either with mature lymphocytes or haematopoietic stem cells. This work provides crucial information for the follow up of current and future GT trials based on genetic modifications of haematopoietic cells.

Accompanying Closeup
Parachuting in the epigenome: the biology of gene vector insertion profiles in the context of clinical trials
Christopher Baum
EMBO Mol Med 2011, 3(2), 75-77


Correction of β-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients
Emanuela Anna Roselli, Riccardo Mezzadra, Marta Claudia Frittoli, Giulietta Maruggi, Erika Biral, Fulvio Mavilio, Fabrizio Mastropietro, Antonio Amato, Giovanni Tonon, Chiara Refaldi, Maria Domenica Cappellini, Marco Andreani, Guido Lucarelli, Maria Grazia Roncarolo, Sarah Marktel, Giuliana Ferrari
EMBO Mol Med 2010, 2(8), 315-328

EMBO Molecular Medicine - Correction of ß-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients

β-Thalassemia leads to anemia and death in the first year of life unless regular transfusions are administered. So far, allogeneic bone marrow transplantation (BMT) is the only curative treatment, but it is limited to less than 25% of patients. Gene therapy, based on autologous transplantation of genetically corrected hematopoietic stem cells, represents a promising alternative for patients lacking a suitable donor. This study provides solid preclinical data of efficacy and safety of the GLOBE-based gene therapy approach to β-thalassemia.

Accompanying Closeup
Gaining the hard yard: pre-clinical evaluation of lentiviral-mediated gene therapy for the treatment of β-thalassemia
Michael D. Milsom, David A. Williams
EMBO Mol Med 2010, 2(8), 291-293

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