Genetics, Gene Therapy & Genetic Disease
- 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.
- Successful correction of hemophilia by CRISPR/Cas9 genome editing in vivo: delivery vector and immune responses are the key to success
Hemophilia B is a serious hemostasis disorder due to mutations of the factor IX gene in the X chromosome. Gene therapy has gained momentum in recent years as a therapeutic option for hemophilia B. In hemophilia, reconstitution with a mere 1–2% of the clotting factor improves the quality of life, while 5–20% suffices to ameliorate the bleeding disorder. A paper by Guan et al (2016) in this issue of EMBO Molecular Medicine reports on the direct CRISPRs/Cas9‐mediated correction in the liver of a hemophilia‐causing point mutation in FIX.
See also: Y Guan et al (May 2016)
Nguyen and Anegon discuss the recent Guan et al paper in this issue of EMBO Molecular Medicine describing the successful correction of hemophilia B in a mouse model by CRISPR/Cas9 genome editing in vivo.
- © 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.
ICI - Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe‐affected non‐human primates by intracerebral lentiviral gene therapy
- Vasco Meneghini1,7,
- Annalisa Lattanzi1,8,
- Luigi Tiradani1,
- Gabriele Bravo1,
- Francesco Morena2,
- Francesca Sanvito3,
- Andrea Calabria1,
- John Bringas4,
- Jeanne M Fisher‐Perkins5,
- Jason P Dufour5,
- Kate C Baker5,
- Claudio Doglioni3,6,
- Eugenio Montini1,
- Bruce A Bunnell5,
- Krystof Bankiewicz4,†,
- Sabata Martino2,
- Luigi Naldini1,6 and
- Angela Gritti*,1
- 1San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- 2Department of Chemistry, Biology and Biotechnologies, Biochemistry and Molecular Biology Unit, University of Perugia, Perugia, Italy
- 3Anatomy and Histopathology Department, San Raffaele Scientific Institute, Milano, Italy
- 4University of California San Francisco (UCSF), San Francisco, CA, USA
- 5Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, LA, USA
- 6Vita‐Salute San Raffaele University, Milan, Italy
- 7Institute Imagine, Paris, France
- 8Genethon, Evry Cedex, France
- ↵*Corresponding author. Tel: +39 02 2643 4623; Fax: +39 02 2643 4668; E‐mail: gritti.angela{at}hsr.it
Report on the safety and efficacy of clinically relevant intracerebral gene therapy to deliver lysosomal enzymes in non‐human primates (NHP) and first evidence of efficacy in a Krabbe‐affected NHP recapitulating human globoid cell leukodystrophy.
Synopsis
Report on the safety and efficacy of clinically relevant intracerebral gene therapy to deliver lysosomal enzymes in non‐human primates (NHP) and first evidence of efficacy in a Krabbe‐affected NHP recapitulating human globoid cell leukodystrophy.
Two intracerebral injections of low doses of therapeutic lentiviral vectors (LV.hARSA, LV.hGALC) performed in juvenile NHP (to mimic the potential treatment of infantile/early juvenile patients) were well tolerated, with undetectable immune response or genotoxicity related to LV integration.
Efficient gene transfer and transgene expression were observed in oligodendrocytes (in addition to neurons and astrocytes), which are hardly transduced by other vector types.
Stable and widespread supraphysiological and close to physiological enzymatic activities were measured in normal animals and in the Krabbe‐affected NHP, respectively.
Neurobehavioral assessment showed a progressive increase of motor scores in the LV.hGALC‐treated Krabbe NHP, with values close to the mean observed in normal animals at 3 months post‐gene therapy.
The extent of ARSA and GALC activity in CNS tissues post‐gene therapy is expected to provide benefit if achieved in human patients, since ≈ 10% of physiological enzymatic activity would ensure a normal phenotype.
EMBO Mol Med (2016) 8: 489–510
- Received September 11, 2015.
- Revision received February 22, 2016.
- Accepted March 1, 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.
ICI - CRISPR/Cas9‐mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse
- Yuting Guan1,†,
- Yanlin Ma*,2,3,†,
- Qi Li2,
- Zhenliang Sun4,
- Lie Ma1,
- Lijuan Wu1,
- Liren Wang1,
- Li Zeng1,
- Yanjiao Shao1,
- Yuting Chen1,
- Ning Ma2,
- Wenqing Lu1,
- Kewen Hu1,
- Honghui Han5,
- Yanhong Yu3,
- Yuanhua Huang2,
- Mingyao Liu*,1,6 and
- Dali Li*,1
- 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- 2Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University Hainan Medical University, Haikou, China
- 3Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- 4Fengxian Hospital affiliated to Southern Medical University, Shanghai, China
- 5Bioray Laboratories Inc., Shanghai, China
- 6Department of Molecular and Cellular Medicine, The Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA
- ↵*
Corresponding author. Tel: +86 898 66776091; E‐mail: mayl1990{at}foxmail.com
Corresponding author. Tel: +86 021 54345014; E‐mail: myliu{at}bio.ecnu.edu.cn
Corresponding author. Tel: +86 021 24206824; E‐mail: dlli{at}bio.ecnu.edu.cn
↵† These authors contributed equally to this work
CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B.
Synopsis
CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B.
Identification a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene.
Generation of three distinct genetically modified mouse models and confirmation that the mouse harboring the novel Y371D mutation is a new hemophilia B model.
Hepatic in situ correction of the point mutation in the F9 allele via CRISPR/Cas9‐mediated genome editing was sufficient to restore hemostasis in hemophilia B mice.
EMBO Mol Med (2016) 8: 477–488
- Received November 8, 2015.
- Revision received February 17, 2016.
- Accepted February 18, 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.
ICI - Mitochondrial disorders in children: toward development of small‐molecule treatment strategies
- Werner JH Koopman1,2,
- Julien Beyrath3,
- Cheuk‐Wing Fung4,5,
- Saskia Koene4,
- Richard J Rodenburg4,
- Peter HGM Willems1,2 and
- Jan AM Smeitink*,2,3,4
- 1Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- 2Centre for Systems Biology and Bioenergetics, Radboud University Medical Center, Nijmegen, The Netherlands
- 3Khondrion BV, Nijmegen, The Netherlands
- 4Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- 5Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
- ↵*Corresponding author. Tel: +31 24 3614430; E‐mail: Jan.Smeitink{at}Radboudumc.nl
Authoritative, comprehensive overview on pediatric mitochondrial disorders including discussion of current directions and strategies for drug development. A desktop resource for basic, translational, and clinical researchers.
EMBO Mol Med (2016) 8: 311–327
- Received December 7, 2015.
- Revision received February 5, 2016.
- Accepted February 11, 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.
- Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability
- Andrew Dauber1,
- María T Muñoz‐Calvo2,3,
- Vicente Barrios2,3,
- Horacio M Domené4,
- Soren Kloverpris5,
- Clara Serra‐Juhé6,
- Vardhini Desikan7,
- Jesús Pozo2,3,
- Radhika Muzumdar8,
- Gabriel Á Martos‐Moreno2,3,
- Federico Hawkins9,
- Héctor G Jasper4,
- Cheryl A Conover10,
- Jan Frystyk11,12,
- Shoshana Yakar13,
- Vivian Hwa1,
- Julie A Chowen2,3,
- Claus Oxvig5,
- Ron G Rosenfeld14,15,
- Luis A Pérez‐Jurado6 and
- Jesús Argente*,2,3
- 1Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- 2Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain
- 3Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain
- 4Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
- 5Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- 6Genetics Unit, Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III, Barcelona, Spain
- 7Department of Pediatrics, Division of Pediatric Endocrinology, New York Medical College, Valhalla NY, USA
- 8Division of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- 9Department of Endocrinology, Hospital Universitario 12 de Octubre Universidad Complutense de Madrid, Madrid, Spain
- 10Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
- 11Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
- 12Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- 13Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
- 14Oregon Health and Science University, Portland, OR, USA
- 15STAT5 LLC, Los Altos, CA, USA
- ↵*Corresponding author. Tel: +34 91 5035912; Fax: +34 91 5035939; E‐mail: jesus.argente{at}uam.es
Pregnancy‐associated plasma protein‐A2 (PAPP‐A2) is a highly specific protease for the cleavage of insulin‐like growth factor (IGF)‐binding proteins. PAPP‐A2 homozygous loss‐of‐function mutations alter IGF‐I transport and cause growth defects in patients.
Synopsis
Pregnancy‐associated plasma protein‐A2 (PAPP‐A2) is a highly specific protease for the cleavage of insulin‐like growth factor (IGF)‐binding proteins. PAPP‐A2 homozygous loss‐of‐function mutations alter IGF‐I transport and cause growth defects in patients.
This new syndrome of short stature is characterized by:
Mild but progressive postnatal growth failure, moderate microcephaly, and decreased bone density with mild skeletal abnormalities.
Elevated concentrations of circulating total IGF‐I, IGFBP‐3, and IGFBP‐5, acid labile subunit, IGF‐II, and basal insulin, with increased ternary complex formation.
Very low levels of free IGF‐I and bioactive IGF.
EMBO Mol Med (2016) 8: 363–374
- Received November 27, 2015.
- Revision received January 18, 2016.
- Accepted January 25, 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.
- Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing
- Annalisa Buniello*,1,2,
- Neil J Ingham1,2,
- Morag A Lewis1,2,
- Andreea C Huma2,
- Raquel Martinez‐Vega2,3,4,
- Isabel Varela‐Nieto3,4,
- Gema Vizcay‐Barrena5,
- Roland A Fleck5,
- Oliver Houston6,
- Tanaya Bardhan6,
- Stuart L Johnson6,
- Jacqueline K White2,
- Huijun Yuan7,
- Walter Marcotti6 and
- Karen P Steel*,1,2
- 1Wolfson Centre For Age‐Related Diseases, King's College London, London, UK
- 2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
- 3Instituto de Investigaciones Biomédicas Alberto Sols, CSIC‐UAM, Madrid, Spain
- 4Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 761, Instituto de Salud Carlos III, Madrid, Spain
- 5Centre for Ultrastructural Imaging, King's College London, London, UK
- 6Department of Biomedical Science, University of Sheffield, Sheffield, UK
- 7Medical Genetics Center, Southwest Hospital Third Military Medical University, Chongqing, China
- ↵*
Corresponding author. Tel: +44 207 848 6803; E‐mail: annalisa.buniello{at}kcl.ac.uk
Corresponding author. Tel: +44 207 848 6203; E‐mail: karen.steel{at}kcl.ac.uk
WBP2 was found to underlie deafness in mouse and patients. Wbp2‐deficient mice were used as a genetic tool to gain insight into the functional link between hormonal signalling and hearing impairment.
Synopsis
WBP2 was found to underlie deafness in mouse and patients. Wbp2‐deficient mice were used as a genetic tool to gain insight into the functional link between hormonal signalling and hearing impairment.
WBP2 mutations lead to deafness in mouse and humans.
In the Wbp2‐mutant mouse, the earliest abnormality is swelling of afferent nerve endings below inner hair cells and mice show progressive high‐frequency hearing loss.
Wbp2 deficiency leads to reduced expression of estrogen and progesterone receptors in the cochlea and disrupted expression of key post‐synaptic proteins.
EMBO Mol Med (2016) 8: 191–207
- Received June 9, 2015.
- Revision received December 18, 2015.
- Accepted December 21, 2015.
- © 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.
- Amyloid‐β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing
There is increasing evidence that common molecular pathways in neurons are closely linked with mitochondrial function and that mitochondrial dysfunction is connected to various forms of neurodegenerative diseases. For instance, mitochondria are involved in amyloid‐β (Aβ) deposition in Alzheimer's disease, although the exact molecular pathways remain largely unknown. Brunetti et al (2015) in this issue of EMBO Molecular Medicine provide a novel link between Aβ accumulation and mitochondria. A pathogenic mutation in a Norwegian family in the mitochondrial metallopeptidase PITRM1 is found to underlie a novel mitochondrial neurodegenerative phenotype associated with Aβ accumulation.
See also: D Brunetti et al (March 2016)
Boczonadi and Horvath comment on the Brunetti et al's paper in this issue describing a mitochondrial metallopeptidase PITRM1 pathogenic mutation in a Norwegian family, underlying a novel mitochondrial neurodegenerative phenotype with Aβ accumulation.
- © 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 awesome lysosome
- 1Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- 2Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy
- 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- 4Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA
In the early 50s, Christian De Duve identified a new cellular structure, the lysosome, defined as the cell's “suicide bag” (de Duve, 2005). Sixty years later, it is clear that the lysosome greatly exceeded the expectations of its discoverer. Over 50 different types of lysosomal storage diseases have been identified, each due to the deficiency or malfunction of a specific lysosomal protein. In addition, an important role of the lysosome has been unveiled in several common human diseases, such as cancer, obesity, neurodegenerative diseases, and infection. Recent studies have led to the identification of a lysosome‐to‐nucleus signaling pathway and a lysosomal gene network that regulate cellular clearance and energy metabolism. These observations have opened a completely new field of research and changed our traditional view of the lysosome from a dead‐end organelle to a control center of cell metabolism. An important challenge for the future will be to exploit these discoveries to identify modulators of lysosomal function that may be used to treat human diseases.
The 2016 Louis‐Jeantet Prize for Medicine winner Andrea Ballabio offers an account of the current state of the art of lysosomal research in cell biology and disease.
EMBO Mol Med (2016) 8: 73–76
- © 2015 The Author. 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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