Genetics, Gene Therapy & Genetic Disease
- Modified Atkins diet induces subacute selective ragged‐red‐fiber lysis in mitochondrial myopathy patients
- Sofia Ahola1,
- Mari Auranen1,2,
- Pirjo Isohanni1,
- Satu Niemisalo3,
- Niina Urho2,
- Jana Buzkova1,
- Vidya Velagapudi4,
- Nina Lundbom5,
- Antti Hakkarainen5,
- Tiina Muurinen6,
- Päivi Piirilä6,
- Kirsi H Pietiläinen2,7 and
- Anu Suomalainen (anu.wartiovaara{at}helsinki.fi)*,1,2,8
- 1Research Program of Molecular Neurology, Biomedicum Helsinki University of Helsinki, Helsinki, Finland
- 2Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- 3Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
- 4Metabolomics Unit, Institute for Molecular Medicine Finland FIMM University of Helsinki, Helsinki, Finland
- 5Department of Radiology, University of Helsinki and HUS Radiology Helsinki Medical Imaging Center, Helsinki, Finland
- 6Department of Clinical Physiology and Nuclear Medicine, Laboratory of Clinical Physiology, Helsinki University Hospitals, Helsinki, Finland
- 7Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland
- 8Neuroscience Center, University of Helsinki, Helsinki, Finland
- ↵*Corresponding author. Tel: +358 9 47171965; E‐mail: anu.wartiovaara{at}helsinki.fi
High‐fat, low‐carbohydrate modified Atkins diet (mAD) is a common weight‐loss method, found to ameliorate mitochondrial myopathy in mice. In human patients, mAD induces muscle damage, especially of ragged‐red fibers, the most affected by the disease.
Synopsis
High‐fat, low‐carbohydrate modified Atkins diet (mAD) is a common weight‐loss method, found to ameliorate mitochondrial myopathy in mice. In human patients, mAD induces muscle damage, especially of ragged‐red fibers, the most affected by the disease.
mAD causes subacute lysis of respiratory chain‐deficient fibers in mitochondrial myopathy.
All mitochondrial myopathy patients experienced similar muscle symptoms, independently of their disease mutation.
Ragged‐red fibers (RRFs) are unable to use fuels other than glucose.
Short dietary intervention could be a tool to reduce RRF amount.
The Atkins diet may thus cause muscle damage to a population subgroup with subclinical mitochondrial disease.
EMBO Mol Med (2016) 8: 1234–1247
- Received May 10, 2016.
- Revision received August 10, 2016.
- Accepted August 12, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Blocking sense‐strand activity improves potency, safety and specificity of anti‐hepatitis B virus short hairpin RNA
- Thomas Michler1,2,
- Stefanie Große3,4,
- Stefan Mockenhaupt3,4,6,
- Natalie Röder1,
- Ferdinand Stückler5,
- Bettina Knapp5,
- Chunkyu Ko1,
- Mathias Heikenwalder1,7,
- Ulrike Protzer*,1,2,† and
- Dirk Grimm*,3,4,†
- 1Institute of Virology, Technische Universität München/Helmholtz Zentrum München, München, Germany
- 2German Center for Infection Research (DZIF), partner site München, München, Germany
- 3Department of Infectious Diseases/Virology, Cluster of Excellence CellNetworks, Heidelberg University Hospital, Heidelberg, Germany
- 4BioQuant, University of Heidelberg, Heidelberg, Germany
- 5Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
- 6School of Biological Sciences, Nanyang Technological University, Singapore City, Singapore
- 7 Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- ↵*
Corresponding author. Tel: +49 89 4140 6821; E‐mails: protzer{at}tum.de; protzer{at}helmholtz-muenchen.de
Corresponding author. Tel: +49 6221 5451339; E‐mail: dirk.grimm{at}bioquant.uni-heidelberg.de
↵† These authors contributed equally to this work
RNAi is a powerful technology to suppress pathogens like hepatitis B virus (HBV), yet clinical translation requires better efficiency, safety and specificity. Here, a new solution is provided in the form of AAV vectors expressing anti‐HBV shRNAs together with an inhibitor of the shRNA sense strand.
Synopsis
RNAi is a powerful technology to suppress pathogens like hepatitis B virus (HBV), yet clinical translation requires better efficiency, safety and specificity. Here, a new solution is provided in the form of AAV vectors expressing anti‐HBV shRNAs together with an inhibitor of the shRNA sense strand.
Hepatic AAV/shRNA expression yields potent target knockdown but can be toxic due to saturation of the RNAi pathway and off‐target dysregulation of cellular genes by the shRNA sense strand.
One possible solution is to embed the shRNA in a miRNA scaffold, which reduces toxicity but also efficiency of HBV target knockdown.
Alternatively, over‐expression of the rate‐limiting RNAi factor Ago2 from the same AAV vector can ameliorate toxicity without compromising efficacy.
A novel strategy yielding best results is co‐delivery of a “tough decoy” (TuD) that blocks shRNA sense‐strand activity and concurrently enhances vector potency, safety and specificity in vivo.
EMBO Mol Med (2016) 8: 1082–1098
- Received December 27, 2015.
- Revision received July 3, 2016.
- Accepted July 5, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
- Zhaiyi Zhang1,†,
- Manli Shen1,†,
- Paul J Gresch2,
- Masoud Ghamari‐Langroudi3,
- Alexander G Rabchevsky4,
- Ronald B Emeson3 and
- Stefan Stamm*,1
- 1Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
- 2Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
- 3Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
- 4Spinal Cord & Brain Injury, Research Center, University of Kentucky, Lexington, KY, USA
- ↵*Corresponding author. Tel: +1859 323 0896; E‐mail: stefan{at}stamms-lab.net
↵† These authors contributed equally to this work
The serotonin 2C receptor regulates food uptake and undergoes alternative pre‐mRNA splicing; the ratio of the two spliced isoforms (truncated versus full length) controls the activity of serotonergic neurons. An oligonucleotide promotes the formation of the full‐length receptor and reduces food intake.
Synopsis
The serotonin 2C receptor regulates food uptake and undergoes alternative pre‐mRNA splicing; the ratio of the two spliced isoforms (truncated versus full length) controls the activity of serotonergic neurons. An oligonucleotide promotes the formation of the full‐length receptor and reduces food intake.
The ratio of serotonin 2C receptor splicing isoforms controls food intake.
This ratio can be changed using a synthetic oligonucleotide.
The oligonucleotide mimics a naturally trans‐acting RNA, SNORD115, that is not expressed in Prader–Willi syndrome, a genetic form of obesity.
Through heterodimerization with other receptors, the isoform ratio could impact on various receptor systems contributing to Prader–Willi syndrome.
EMBO Mol Med (2016) 8: 878–894
- Received November 3, 2015.
- Revision received May 27, 2016.
- Accepted June 9, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome
- Alexandre Janer1,2,
- Julien Prudent2,3,†,
- Vincent Paupe1,2,†,
- Somayyeh Fahiminiya1,
- Jacek Majewski1,
- Nicolas Sgarioto2,
- Christine Des Rosiers4,5,
- Anik Forest4,5,
- Zhen‐Yuan Lin6,
- Anne‐Claude Gingras6,7,
- Grant Mitchell8,
- Heidi M McBride2,3 and
- Eric A Shoubridge*,1,2
- 1Department of Human Genetics, McGill University, Montreal, QC, Canada
- 2Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- 3Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- 4Department of Nutrition, Université de Montréal, Montreal, QC, Canada
- 5Research Centre, Montreal Heart Institute, Montreal, QC, Canada
- 6Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- 7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- 8Division of Medical Genetics, Department of Pediatrics, CHU Sainte‐Justine and Université de Montréal, Montreal, QC, Canada
- ↵*Corresponding author. Tel: +1 514 398 1997; Fax: +1 514 398 1509; E‐mail: eric{at}ericpc.mni.mcgill.ca
Whole‐exome sequencing in a Leigh syndrome patient identified mutations in SLC25A46, a degenerate member of the mitochondrial metabolite transport family, linking altered mitochondrial dynamics to early‐onset neurodegenerative disease.
Synopsis
Whole‐exome sequencing in a Leigh syndrome patient identified mutations in SLC25A46, a degenerate member of the mitochondrial metabolite transport family, linking altered mitochondrial dynamics to early‐onset neurodegenerative disease.
Loss of SLC25A46 results in mitochondrial hyperfusion and striking changes in mitochondrial architecture.
SLC25A46 is an outer membrane protein that interacts with MFN2, OPA1, the MICOS complex, and the EMC complex in the ER.
Loss of SLC25A46 results in altered ER morphology and marked changes in the phospholipid composition of the mitochondrial membranes.
Loss of SLC25A46 results in premature cellular senescence in dividing cells.
EMBO Mol Med (2016) 8: 1019–1038
- Received December 21, 2015.
- Revision received June 7, 2016.
- Accepted June 9, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- The decision‐making process and criteria in selecting candidate drugs for progeria clinical trials
- Leslie B Gordon (leslie_gordon{at}brown.edu)1,2,
- Mark W Kieran3,
- Monica E Kleinman1 and
- Tom Misteli4
- 1Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- 2Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA
- 3Dana‐Farber Boston Children's Cancer and Blood Disorder Center, Dana‐Farber Cancer Institute, Boston, MA, USA
- 4National Cancer Institute, NIH, Bethesda, MD, USA
Hutchinson–Gilford progeria syndrome (progeria) is an extremely rare premature aging disease with a population prevalence of 1 in 20 million. Nevertheless, propelled by the discovery of a causal mutation in the lamin A/C gene (LMNA) (De Sandre‐Giovannoli et al, 2003; Eriksson et al, 2003) and strong patient advocacy (Gordon & Gordon, 2014), progeria has rapidly become a vibrant field of study, attracting a wide range of researchers from basic cell biologists to clinicians.
Conducting clinical trials for children with progeria or any rare disease is especially complex. However, given the lack of treatments and the dismal outcomes, any treatment that meets suitable standards to advance to trial should be vigorously pursued.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Brain endothelial cell‐targeted gene therapy of neurovascular disorders
- Serena Marchiò1,2,3,4,
- Richard L Sidman5,
- Wadih Arap (warap{at}salud.unm.edu)6,† and
- Renata Pasqualini (rpasqual{at}salud.unm.edu)1,2,†
- 1University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA
- 2Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
- 3Department of Oncology, University of Turin, Candiolo, Italy
- 4Candiolo Cancer Institute‐FPO, IRCCS, Candiolo, Italy
- 5Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- 6Division of Hematology and Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
↵† These authors contributed equally
Neurovascular disorders are difficult to treat due to the blood–brain barrier (BBB), which prevents delivery of most drugs from the blood into the brain. Gene therapy can potentially overcome this barrier, but classical vectors are neither efficient nor specific enough to provide long‐lasting treatment or avoid off‐target effects. In this issue of EMBO Molecular Medicine, Körbelin et al (2016) describe an engineered adeno‐associated virus (AAV) with exceptional tropism for the brain that restores a normal phenotype in a mouse model of incontinentia pigmenti (IP), a severe human genetic disorder of brain vasculature.
See also: J Körbelin et al (June 2016)
Commentary on the paper by Körbelin et al in this issue of EMBO Molecular Medicine, describing an engineered adeno‐associated virus (AAV) with exceptional tropism for the brain that restores a normal phenotype in a mouse incontinentia pigmenti model.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Safe engineering of CAR T cells for adoptive cell therapy of cancer using long‐term episomal gene transfer
- Chuan Jin1,
- Grammatiki Fotaki1,‡,
- Mohanraj Ramachandran1,‡,
- Berith Nilsson1,
- Magnus Essand*,1,† and
- Di Yu*,1,†
- 1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- ↵*
Corresponding author. Tel: +46 18 471 4535; E‐mail: magnus.essand{at}igp.uu.se
Corresponding author. Tel: +46 18 471 4524; E‐mail: di.yu{at}igp.uu.se
CAR T cells for cancer immunotherapy are commonly engineered ex vivo via a viral vector with integration of the transgene and possible tumorigenic risk. A new vector, NILV‐S/MAR, allows long‐term episomal engineering of T cells to reduce such risk.
Synopsis
CAR T cells for cancer immunotherapy are commonly engineered ex vivo via a viral vector with integration of the transgene and possible tumorigenic risk. A new vector, NILV‐S/MAR, allows long‐term episomal engineering of T cells to reduce such risk.
The NILV‐S/MAR vector is maintained as self‐replicating DNA circles in engineered T cells, which are passed on to daughter cells.
The NILV‐S/MAR vector is suitable for both long‐term transgene expression and delivery of shRNA for gene silencing.
CAR T cells engineered with the NILV‐S/MAR vector exhibit phenotype and function similar to CAR T cells engineered by a conventional lentiviral vector.
The NILV‐S/MAR vector can be used for the safe engineering of stem cells as well as induced pluripotent stem cells.
EMBO Mol Med (2016) 8: 702–711
- Received September 30, 2015.
- Revision received April 4, 2016.
- Accepted April 8, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- A brain microvasculature endothelial cell‐specific viral vector with the potential to treat neurovascular and neurological diseases
- Jakob Körbelin1,
- Godwin Dogbevia2,
- Stefan Michelfelder1,
- Dirk A Ridder2,
- Agnes Hunger1,
- Jan Wenzel2,
- Henning Seismann1,
- Melanie Lampe1,
- Jacqueline Bannach2,
- Manolis Pasparakis3,
- Jürgen A Kleinschmidt4,
- Markus Schwaninger2,† and
- Martin Trepel*,1,5,†
- 1Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
- 2Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
- 3Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), Institute for Genetics University of Cologne, Cologne, Germany
- 4Department of Tumor Virology, German Cancer Research Center, Heidelberg, Germany
- 5Department of Hematology and Oncology, Augsburg Medical Center, Augsburg, Germany
- ↵*Corresponding author. Tel: +49 821 400 2353; Fax: +49 821 400 3344; E‐mail: m.trepel{at}uke.de
↵† These authors contributed equally to this work
A capsid AAV2 mutant, AAV‐BR1, with tropism for the neurovascular endothelium, generated by selecting an AAV2 display peptide library in vivo, holds promise as a gene therapy vector for neurovascular and potentially other central nervous system diseases.
Synopsis
A capsid AAV2 mutant, AAV‐BR1, with tropism for the neurovascular endothelium, generated by selecting an AAV2 display peptide library in vivo, holds promise as a gene therapy vector for neurovascular and potentially other central nervous system diseases.
Capsid mutants with a specific redirected tropism can be selected from AAV display peptide libraries in vivo.
One mutant, AAV‐BR1, effectively transduces neurovascular (blood–brain barrier‐associated) endothelial cells in vivo and in vitro.
AAV‐BR1 can be used to ameliorate the severe neurological impairments in a mouse model of incontinentia pigmenti.
EMBO Mol Med (2016) 8: 609–625
- Received November 19, 2015.
- Revision received March 22, 2016.
- Accepted March 23, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Ethical and legal issues in mitochondrial transfer
The US National Academies of Science, Engineering and Medicine recently provided conditional endorsement for mitochondrial transfer. While its approach is more conservative in some respects than that of the United Kingdom (which passed its own regulations in 2015), it marks a significant policy development for a potentially large implementer of this emerging intervention. In this perspective, we consider some of the ethical and legal aspects of these policy responses.
A timely commentary on the ethical and legal issues in mitochondrial transfer/replacement techniques in the aftermath of the recent UK and US regulations.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty
- Sasha R Howard1,†,
- Leonardo Guasti1,†,
- Gerard Ruiz‐Babot1,
- Alessandra Mancini1,
- Alessia David2,
- Helen L Storr1,
- Lousie A Metherell1,
- Michael JE Sternberg2,
- Claudia P Cabrera3,4,
- Helen R Warren4,5,
- Michael R Barnes3,4,
- Richard Quinton6,
- Nicolas de Roux7,8,9,
- Jacques Young10,11,12,13,
- Anne Guiochon‐Mantel10,11,12,
- Karoliina Wehkalampi14,
- Valentina André15,
- Yoav Gothilf16,
- Anna Cariboni15,17 and
- Leo Dunkel*,1
- 1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 2Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK
- 3Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 4NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK
- 5Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
- 6Institute of Genetic Medicine University of Newcastle‐upon‐Tyne, Newcastle‐upon‐Tyne, UK
- 7Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France
- 8Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
- 9Laboratoire de Biochimie, Assistance Publique‐Hôpitaux de Paris, Hôpital Robert Debré, Paris, France
- 10Univ Paris‐Sud, Le Kremlin Bicêtre, France
- 11INSERM UMR‐1185, Le Kremlin Bicêtre, France
- 12Assistance Publique‐Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin‐Bicêtre, France
- 13Department of Reproductive Endocrinology, Bicêtre Hospital, Le Kremlin‐Bicêtre, France
- 14Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- 15Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- 16Department of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel‐Aviv University, Tel Aviv, Israel
- 17Institute of Ophthalmology, University College London (UCL), London, UK
- ↵*Corresponding author. Tel: +44 207 882 6235; Fax: +44 207 882 6197; E‐mail: l.dunkel{at}qmul.ac.uk
↵† These authors contributed equally to this work
Self‐limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans.
Synopsis
Self‐limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans.
Pathogenic mutations in IGSF10 are found in patients with self‐limited delayed puberty.
IGSF10 is a gene of previously unclear function with no known human mutations.
IGSF10 is expressed within the nasal mesenchyme during fetal development, in a pattern similar to known chemokines that direct migrational GnRH neurons to the hypothalamus.
Knockdown of IGSF10 led to a reduced migration of GnRH neurons in vitro and in a transgenic zebrafish model.
IGSF10 loss‐of‐function mutations were also identified in patients with hypothalamic amenorrhea, suggesting an overlapping genetic and mechanistic basis between different types of functional hypogonadotropic hypogonadism, including DP and hypothalamic amenorrhea.
EMBO Mol Med (2016) 8: 626–642
- Received January 26, 2016.
- Revision received March 1, 2016.
- Accepted March 14, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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