209 results on '"Genetic Enhancement"'
Search Results
2. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
- Author
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Kallanthottathil G. Rajeev, Nicole M. Gaudelli, Yusuf S. Nasrullah, Soumyashree A. Gangopadhyay, Andrew M. Bellinger, Sara P. Garcia, James Madsen, Jamie E. DeNizio, Athul Sanjeev, Lisa N. Kasiewicz, Giuseppe Ciaramella, Aaron Beach, Ellen Rohde, Anne Marie Mazzola, Thomas V. Colace, Kui Wang, Sowmya Iyer, Caroline W. Reiss, Padma Malyala, Steven H. Y. Fan, Victoria Clendaniel, Christopher J. Cheng, Jennifer Lavoie, Taiji Mizoguchi, Yuri Matsumoto, Madeleine Shay, Kiran Musunuru, Leslie E. Stolz, Maurine C. Braun, Chaitali Dutta, Ying K. Tam, Joseph Nneji, Ryan Garrity, Alexandra C. Chadwick, Souvik Biswas, Michael Amaonye, John D. Ganey, Mary R. Stahley, Huilan Ren, Huei-Mei Chen, Kathleen Berth, and Sekar Kathiresan
- Subjects
Male ,0301 basic medicine ,Time Factors ,Genetic enhancement ,030204 cardiovascular system & hematology ,Pharmacology ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genome editing ,Loss of Function Mutation ,In vivo ,Animals ,Humans ,CRISPR ,Gene ,Cells, Cultured ,Gene Editing ,Gene knockdown ,Multidisciplinary ,Cholesterol ,Adenine ,PCSK9 ,Cholesterol, LDL ,Mice, Inbred C57BL ,Macaca fascicularis ,030104 developmental biology ,Liver ,chemistry ,Models, Animal ,Hepatocytes ,Mutagenesis, Site-Directed ,Female ,CRISPR-Cas Systems ,Proprotein Convertase 9 - Abstract
Gene-editing technologies, which include the CRISPR–Cas nucleases1–3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs. In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.
- Published
- 2021
3. Gene therapies close in on a cure for sickle-cell disease
- Author
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Michael Eisenstein
- Subjects
2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Genetic enhancement ,Cell ,Genomics ,Disease ,Bioinformatics ,medicine.anatomical_structure ,medicine ,business ,Gene - Abstract
As multiple genetic strategies advance through the clinic, important safety questions remain to be answered. As multiple genetic strategies advance through the clinic, important safety questions remain to be answered.
- Published
- 2021
4. Gene therapy is facing its biggest challenge yet
- Author
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Heidi Ledford
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Genetic enhancement ,MEDLINE ,HIV Infections ,Anemia, Sickle Cell ,Disease ,030105 genetics & heredity ,0603 philosophy, ethics and religion ,South Africa ,Young Adult ,03 medical and health sciences ,Genome editing ,medicine ,Humans ,Healthcare Disparities ,Young adult ,Intensive care medicine ,Developing Countries ,Gene Editing ,Multidisciplinary ,business.industry ,beta-Thalassemia ,Genetic Therapy ,Health Care Costs ,06 humanities and the arts ,Traction (orthopedics) ,eye diseases ,sense organs ,060301 applied ethics ,business - Abstract
After finally gaining traction as a potential treatment for certain genetic disorders, gene therapy tackles the challenge of sickle-cell disease. After finally gaining traction as a potential treatment for certain genetic disorders, gene therapy tackles the challenge of sickle-cell disease.
- Published
- 2019
5. The Power of Spheres
- Author
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Chad A. Mirkin, Kacper Skakuj, and Christine R. Laramy
- Subjects
chemistry.chemical_compound ,Multidisciplinary ,Chemistry ,Genetic enhancement ,fungi ,Cancer research ,food and beverages ,RNA ,DNA ,Brain cancer - Abstract
DNA or RNA molecules, arranged into spherical shapes, can attack brain cancers and other illnesses that evade conventional drug design. DNA or RNA molecules, arranged into spherical shapes, can attack brain cancers and other illnesses that evade conventional drug design.
- Published
- 2019
6. Gene Therapy Is Coming of Age
- Author
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Lauren Gravitz
- Subjects
Blood cancer ,medicine.medical_specialty ,Multidisciplinary ,Standard care ,business.industry ,Genetic enhancement ,medicine ,Intensive care medicine ,business - Abstract
Various approaches are approved for treating blood cancers and a few rare disorders—they may soon become standard care. Various approaches are approved for treating blood cancers and a few rare disorders—they may soon become standard care.
- Published
- 2021
7. Landmark CRISPR trial shows promise against deadly disease
- Author
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Heidi Ledford
- Subjects
Multidisciplinary ,business.industry ,Genetic enhancement ,Medicine ,CRISPR ,Disease ,Bioinformatics ,business - Abstract
Administering gene-editing treatment directly into the body could be a safe and effective way to treat a rare, life-threatening condition. Administering gene-editing treatment directly into the body could be a safe and effective way to treat a rare, life-threatening condition.
- Published
- 2021
8. Gene therapy could offer an inclusive cure for cystic fibrosis
- Author
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Roxanne Khamsi
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Multidisciplinary ,business.industry ,Genetic enhancement ,MEDLINE ,nutritional and metabolic diseases ,Disease ,medicine.disease ,Cystic fibrosis ,nervous system diseases ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Diabetes mellitus ,Medicine ,030212 general & internal medicine ,business ,Intensive care medicine - Abstract
After three decades of false starts, gene therapy against the disease is in new clinical trials — and there is even hope of a cure. After three decades of false starts, gene therapy against the disease is in new clinical trials — and there is even hope of a cure.
- Published
- 2020
9. A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene
- Author
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Steven Erwood, Elzbieta Hyatt, Madeleine Durbeej, Prabhpreet S Bassi, Dwi U. Kemaladewi, Dhekra Al-Basha, Kara M Place, Evgueni A. Ivakine, R. Marks, Ronald D. Cohn, Lindsay K, Steven A. Prescott, Rebekah Kember, and Kinga I. Gawlik
- Subjects
0301 basic medicine ,Mutation ,Multidisciplinary ,business.industry ,Transgene ,Genetic enhancement ,Skeletal muscle ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Downregulation and upregulation ,Paralysis ,Congenital muscular dystrophy ,Cancer research ,Medicine ,Muscular dystrophy ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice. MDC1A is caused by mutations in LAMA2 that lead to nonfunctional laminin-α2, which compromises the stability of muscle fibres and the myelination of peripheral nerves. Transgenic overexpression of Lama1, which encodes a structurally similar protein called laminin-α1, ameliorates muscle wasting and paralysis in mouse models of MDC1A, demonstrating its importance as a compensatory modifier of the disease1. However, postnatal upregulation of Lama1 is hampered by its large size, which exceeds the packaging capacity of vehicles that are clinically relevant for gene therapy. We modulate expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis. However, for many disorders it is important to investigate the therapeutic window and reversibility of symptoms. In muscular dystrophies, it has been hypothesized that fibrotic changes in skeletal muscle are irreversible. However, we show that dystrophic features and disease progression were improved and reversed when the treatment was initiated in symptomatic dy2j/dy2j mice with apparent hindlimb paralysis and muscle fibrosis. Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR-dCas9-mediated upregulation of Lama1, which may enable mutation-independent treatment for all patients with MDC1A. This approach has a broad applicability to a variety of disease-modifying genes and could serve as a therapeutic strategy for many inherited and acquired diseases.
- Published
- 2019
10. ‘CRISPR babies’ are still too risky, says influential panel
- Author
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Heidi Ledford
- Subjects
animal structures ,Multidisciplinary ,Genome editing ,Genetic enhancement ,embryonic structures ,MEDLINE ,CRISPR ,Computational biology ,Biology - Abstract
The safety and efficacy of genome editing in human embryos hasn’t been proven, researchers warn. The safety and efficacy of genome editing in human embryos hasn’t been proven, researchers warn.
- Published
- 2020
11. Stem-cell and genetic therapies make a healthy marriage
- Author
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Bianca Nogrady
- Subjects
Multidisciplinary ,business.industry ,General partnership ,Genetic enhancement ,Immunology ,Human immunodeficiency virus (HIV) ,virus diseases ,Medicine ,Stem cell ,business ,medicine.disease_cause ,health care economics and organizations - Abstract
This scientific partnership could fight everything from blood diseases to HIV. This scientific partnership could fight everything from blood diseases to HIV.
- Published
- 2019
12. Hippo pathway deficiency reverses systolic heart failure after infarction
- Author
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Min Zhang, Todd Heallen, Mahdis Rahmani, James T. Willerson, Matthew C. Hill, Yuka Morikawa, John Leach, James F. Martin, and Ana Maria Segura
- Subjects
Quality Control ,0301 basic medicine ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,Genetic enhancement ,Myocardial Infarction ,Infarction ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Biology ,Small hairpin RNA ,Mice ,03 medical and health sciences ,Downregulation and upregulation ,Fibrosis ,Internal medicine ,medicine ,Animals ,Humans ,Hippo Signaling Pathway ,Myocytes, Cardiac ,RNA, Messenger ,Myocardial infarction ,Cell Proliferation ,Mice, Knockout ,Hippo signaling pathway ,Multidisciplinary ,Genetic Therapy ,Anatomy ,medicine.disease ,030104 developmental biology ,Heart failure ,Cardiology ,Heart Failure, Systolic ,Signal Transduction - Abstract
Deletion of the Hippo pathway component Salvador in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function. Previous work has shown that interfering with Hippo signalling during myocardial injury improves heart function in mice. Clinical outcomes of acute myocardial infarction in humans have improved as a result of better emergency care, but chronic heart failure, whereby the heart tissue undergoes pathological remodelling, remains a leading cause of death. James Martin and colleagues now show that the failing heart has a previously unrecognized capacity for repair. They show that blocking Hippo signalling can rescue established heart failure in mice. Deletion of the Hippo pathway component Salvador (Salv) or virus-mediated delivery of Salv short hairpin RNA when ischaemic heart failure is established can improve heart function in mice. The authors attribute the effect to the induction of a reparative genetic program, including increased expression of stress response genes and proliferative genes and preservation of mitochondrial quality control. Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality1. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration2, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.
- Published
- 2017
13. Regulating the gene-therapy revolution
- Author
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Eric Bender
- Subjects
Male ,0301 basic medicine ,Clinical Trials as Topic ,Multidisciplinary ,business.industry ,Drug discovery ,Genetic enhancement ,Genetic Vectors ,Gene Transfer Techniques ,Genetic Therapy ,Dependovirus ,030105 genetics & heredity ,Bioinformatics ,03 medical and health sciences ,Organ Specificity ,Practice Guidelines as Topic ,Government Regulation ,Humans ,Medicine ,Child ,business ,human activities ,Gene - Abstract
The medical regulatory authorities ride a wave of clinical studies for gene therapies. The medical regulatory authorities ride a wave of clinical studies for gene therapies.
- Published
- 2018
14. Collect more data from Africa to improve gene therapy
- Author
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Ambroise Wonkam
- Subjects
2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Genetic enhancement ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Medicine ,Disease ,business ,Virology ,Genetic association - Abstract
Despite the continent being the epicentre of sickle-cell disease, too few Africans are included in genome-wide association studies. Despite the continent being the epicentre of sickle-cell disease, too few Africans are included in genome-wide association studies.
- Published
- 2021
15. Sickle-cell disease
- Author
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Herb Brody
- Subjects
Multidisciplinary ,business.industry ,Genetic enhancement ,African descent ,Medicine ,Disease ,business ,Bioinformatics - Abstract
A condition that affects many people of African descent is finally meeting its therapeutic match. A condition that affects many people of African descent is finally meeting its therapeutic match.
- Published
- 2021
16. Failure of genetic therapies for Huntington’s devastates community
- Author
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Diana Kwon
- Subjects
0301 basic medicine ,Multidisciplinary ,business.industry ,Drug discovery ,Genetic enhancement ,Neurodegeneration ,medicine.disease ,Bioinformatics ,GeneralLiterature_MISCELLANEOUS ,enzymes and coenzymes (carbohydrates) ,03 medical and health sciences ,ComputingMethodologies_PATTERNRECOGNITION ,030104 developmental biology ,0302 clinical medicine ,Software_SOFTWAREENGINEERING ,Mutant protein ,medicine ,business ,030217 neurology & neurosurgery - Abstract
Hopes were high for drugs designed to lower levels of a mutant protein, but development has stalled. Hopes were high for drugs designed to lower levels of a mutant protein, but development has stalled.
- Published
- 2021
17. A menagerie of stem-cell models
- Author
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Jyoti Madhusoodanan
- Subjects
Conservation of Natural Resources ,animal diseases ,Genetic enhancement ,Genetic Vectors ,Induced Pluripotent Stem Cells ,Biology ,Menagerie ,Models, Biological ,behavioral disciplines and activities ,Retina ,Epigenesis, Genetic ,Species Specificity ,Animals ,Humans ,Cloning, Molecular ,Multidisciplinary ,Stem Cells ,Endangered Species ,fungi ,Sciuridae ,food and beverages ,Fibroblasts ,Cellular Reprogramming ,Cell biology ,Models, Animal ,Stem cell ,psychological phenomena and processes ,Transcription Factors - Abstract
When conventional laboratory models fail, stem cells from squirrels, seals and other species can come to researchers’ aid. When conventional laboratory models fail, stem cells from squirrels, seals and other species can come to researchers’ aid.
- Published
- 2020
18. Mitochondrial genome editing gets precise
- Author
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M. Aushev and Mary Herbert
- Subjects
0301 basic medicine ,Mitochondrial DNA ,030219 obstetrics & reproductive medicine ,Multidisciplinary ,Genetic enhancement ,Cytidine deaminase ,Mitochondrion ,Biology ,Genome ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Genome editing ,chemistry ,Organelle ,DNA - Abstract
A bacterial toxin has been found that allows DNA in a cellular organelle called the mitochondrion to be precisely altered. This development could help to combat diseases caused by mutations in mitochondrial DNA. A base editor for mitochondrial DNA.
- Published
- 2020
19. How the gene behind Huntington’s disease could be neutralized
- Author
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Liam Drew
- Subjects
Male ,0301 basic medicine ,Genetic enhancement ,Spinal Puncture ,Hope ,03 medical and health sciences ,Huntington's disease ,medicine ,Animals ,Humans ,Gene Silencing ,RNA, Messenger ,Gene ,Clinical Trials as Topic ,Huntingtin Protein ,Multidisciplinary ,business.industry ,Neurodegeneration ,Brain ,Oligonucleotides, Antisense ,medicine.disease ,Macaca mulatta ,Huntington Disease ,030104 developmental biology ,Antisense oligonucleotides ,Disease Progression ,Cancer research ,Female ,Mutant Proteins ,business - Abstract
Antisense oligonucleotides are providing researchers and patients with fresh hope of targeting the condition’s genetic cause. Antisense oligonucleotides are providing researchers and patients with fresh hope of targeting the condition’s genetic cause.
- Published
- 2018
20. A CRISPR edit for heart disease
- Author
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Anthony King
- Subjects
0301 basic medicine ,Heart Diseases ,Heart disease ,Genetic enhancement ,Hypercholesterolemia ,Myocardial Ischemia ,Disease ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Bioinformatics ,Dystrophin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genome editing ,Animals ,Humans ,Medicine ,CRISPR ,Muscular dystrophy ,Apolipoproteins C ,Angiopoietin-Like Protein 3 ,Gene Editing ,Multidisciplinary ,business.industry ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Cholesterol, LDL ,Genetic Therapy ,medicine.disease ,Muscular Dystrophy, Duchenne ,Stroke ,Disease Models, Animal ,Angiopoietin-like Proteins ,030104 developmental biology ,Amino Acid Substitution ,Apolipoprotein B-100 ,Mutation ,Monoclonal ,Mutation (genetic algorithm) ,Patient Safety ,CRISPR-Cas Systems ,Proprotein Convertase 9 ,business ,Lipoprotein(a) - Abstract
A one-off injection to reduce the risk of cardiovascular disease is now a prospect thanks to advances in gene editing. A one-off injection to reduce the risk of cardiovascular disease is now a prospect thanks to advances in gene editing.
- Published
- 2018
21. Experimental gene therapy frees ‘bubble-boy’ babies from a life of isolation
- Author
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Heidi Ledford
- Subjects
Pediatrics ,medicine.medical_specialty ,Multidisciplinary ,Isolation (health care) ,business.industry ,musculoskeletal, neural, and ocular physiology ,Genetic enhancement ,macromolecular substances ,biochemical phenomena, metabolism, and nutrition ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,nervous system ,medicine ,bacteria ,030212 general & internal medicine ,business ,Severe disorder - Abstract
Treatment restores immune-system function in young children with severe disorder. Treatment restores immune-system function in young children with severe disorder.
- Published
- 2019
22. Gene therapy targets sickle-cell disease
- Author
-
Anna Nowogrodzki
- Subjects
Oncology ,medicine.medical_specialty ,Clinical Trials as Topic ,Multidisciplinary ,business.industry ,Genetic enhancement ,Cell ,06 humanities and the arts ,Disease ,Anemia, Sickle Cell ,Genetic Therapy ,0603 philosophy, ethics and religion ,Medical research ,United States ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Humans ,060301 applied ethics ,Stem cell ,business ,Child - Abstract
The research is promising, but a true cure for this painful condition could be years away. The research is promising, but a true cure for this painful condition could be years away.
- Published
- 2018
23. Designer viruses could be the secret to cheaper and better gene therapy
- Author
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Neil Savage
- Subjects
0301 basic medicine ,Multidisciplinary ,Genetic enhancement ,fungi ,Genetic Vectors ,food and beverages ,Computational biology ,Genetic Therapy ,Biology ,Dependovirus ,Viral vector ,03 medical and health sciences ,Mice ,030104 developmental biology ,Capsid ,Rare Diseases ,Organ Specificity ,Costs and Cost Analysis ,Animals ,Humans ,Gene - Abstract
Researcher and entrepreneur Luk Vandenberghe thinks he can transport genes into cells much more efficiently by improving the viral vectors that carry them. Researcher and entrepreneur Luk Vandenberghe thinks he can transport genes into cells much more efficiently by improving the viral vectors that carry them.
- Published
- 2018
24. Prenatal gene therapy offers the earliest possible cure
- Author
-
Sarah DeWeerdt
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genetic enhancement ,MEDLINE ,03 medical and health sciences ,Mice ,Pregnancy ,Health care ,medicine ,Animals ,Humans ,Intensive care medicine ,health care economics and organizations ,Multidisciplinary ,Fetal Growth Retardation ,Gaucher Disease ,business.industry ,Prenatal Care ,Genetic Therapy ,medicine.disease ,Fetal Diseases ,030104 developmental biology ,Glucosylceramidase ,Female ,business ,human activities - Abstract
Cancelling out an illness before a child is born offers the most potential benefit. Cancelling out an illness before a child is born offers the most potential benefit.
- Published
- 2018
25. CRISPR-based gene therapy dampens pain in mice
- Author
-
Ariana Remmel
- Subjects
0301 basic medicine ,Multidisciplinary ,business.industry ,Genetic enhancement ,Chronic pain ,medicine.disease ,Bioinformatics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Medicine ,CRISPR ,business ,030217 neurology & neurosurgery - Abstract
Targeted approach could lead to an opioid-free way of treating chronic pain. Targeted approach could lead to an opioid-free way of treating chronic pain.
- Published
- 2021
26. CRISPR gene therapy shows promise against blood diseases
- Author
-
Heidi Ledford
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary ,business.industry ,hemic and lymphatic diseases ,Genetic enhancement ,CRISPR ,Medicine ,030212 general & internal medicine ,Computational biology ,030204 cardiovascular system & hematology ,business - Abstract
Researchers report early successes using genetic approaches to treat sickle-cell anaemia and β-thalassaemia. Researchers report early successes using genetic approaches to treat sickle-cell anaemia and β-thalassaemia.
- Published
- 2020
27. Gene therapy returns to centre stage
- Author
-
Luigi Naldini and Naldini, Luigi
- Subjects
Clinical Trials as Topic ,Multidisciplinary ,business.industry ,T-Lymphocytes ,Genetic enhancement ,medicine.medical_treatment ,Gene targeting ,Cancer ,Genetic Therapy ,Immunotherapy ,Hematopoietic Stem Cells ,Bioinformatics ,medicine.disease ,Clinical trial ,Immune system ,Liver ,Organ Specificity ,Neoplasms ,Gene Targeting ,medicine ,Humans ,Stem cell ,business ,Gene - Abstract
Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.
- Published
- 2015
28. First test of in-body gene editing shows promise
- Author
-
Heidi Ledford
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,Multidisciplinary ,Genome editing ,business.industry ,Genetic enhancement ,Medicine ,business ,Bioinformatics ,Test (assessment) ,Rare disease - Abstract
Preliminary results suggest that treatment for rare disease is safe, but its effectiveness is unclear. Preliminary results suggest that treatment for rare disease is safe, but its effectiveness is unclear.
- Published
- 2018
29. CRISPR takes on Huntington's disease
- Author
-
Michael Eisenstein
- Subjects
0301 basic medicine ,Genetics ,Gene Editing ,Mice, Knockout ,Huntingtin Protein ,Multidisciplinary ,Genetic enhancement ,Genetic Therapy ,030105 genetics & heredity ,Biology ,medicine.disease ,03 medical and health sciences ,Disease Models, Animal ,Mice ,030104 developmental biology ,Huntington Disease ,RNAi Therapeutics ,Genome editing ,Huntington's disease ,medicine ,CRISPR ,Animals ,Humans ,CRISPR-Cas Systems ,Trinucleotide Repeat Expansion - Abstract
Gene editing offers the prospect of curing the inherited neurodegenerative condition in a single dose. Gene editing offers the prospect of curing the inherited neurodegenerative condition in a single dose.
- Published
- 2018
30. Powerful enzyme could make CRISPR gene-editing more versatile
- Author
-
Heidi Ledford
- Subjects
chemistry.chemical_classification ,Multidisciplinary ,Enzyme ,Genome editing ,chemistry ,Cas9 ,Genetic enhancement ,CRISPR ,Computational biology ,Biology ,Genome - Abstract
Revamped Cas9 protein could work on more sites in the genome, and with fewer unwanted effects. Revamped Cas9 protein could work on more sites in the genome, and with fewer unwanted effects.
- Published
- 2018
31. Human embryos: Collect reliable data on embryo selection
- Author
-
Charis, Thompson
- Subjects
Gene Editing ,Fetus ,Genetic Enhancement ,Prenatal Diagnosis ,Iceland ,Humans ,Down Syndrome ,Social Change ,Embryo, Mammalian ,Abortion, Eugenic ,Preimplantation Diagnosis - Published
- 2017
32. Change the genes to fix the skin
- Author
-
Kat Arney
- Subjects
0106 biological sciences ,0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,Multidisciplinary ,010608 biotechnology ,Genetic enhancement ,Biology ,Bioinformatics ,01 natural sciences ,Gene ,Prime (order theory) - Abstract
The largest organ in the body is a prime target for gene therapy. The largest organ in the body is a prime target for gene therapy.
- Published
- 2018
33. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice
- Author
-
Laura P. Spector, Nicole K. Paulk, Paul N. Valdmanis, Yufang Shi, Feijie Zhang, Adi Barzel, Kirk Chu, Matthew H. Porteus, Karin M.L. Gaensler, Yong Huang, and Mark A. Kay
- Subjects
Male ,Multidisciplinary ,Ribosomal skipping ,Targeted Gene Repair ,Genetic enhancement ,Transgene ,Gene targeting ,Promoter ,Biology ,Hemophilia B ,Molecular biology ,Article ,Factor IX ,Genome editing ,Gene Targeting ,Animals ,Humans ,Female ,Gene - Abstract
Site-specific gene addition can allow stable transgene expression for gene therapy. When possible, this is preferred over the use of promiscuously integrating vectors, which are sometimes associated with clonal expansion1 and oncogenesis2. Site-specific endonucleases that can induce high rates of targeted genome editing are finding increasing applications in biological discovery and gene therapy3. However, two safety concerns persist: (1) endonuclease-associated adverse effects, both on4 and off-target5,6; and (2) oncogene activation caused by promoter integration, even without nucleases7. Here, we perform recombinant adeno-associated virus (rAAV) mediated promoterless gene targeting without nucleases and demonstrate amelioration of the bleeding diathesis in haemophilia B mice. In particular, we target a promoterless human coagulation factor IX (hF9) gene to the liver-expressed albumin (Alb) locus. hF9 is targeted, along with a preceding 2A-peptide coding sequence, to be integrated just upstream to the Alb stop codon. While hF9 is fused to Alb at the DNA and RNA levels, two separate proteins are synthesized by way of ribosomal skipping. Thus, hF9 expression is linked to robust hepatic albumin expression without disrupting it. We injected an AAV8-hF9 vector into neonatal and adult mice and achieved on-target integration into ~0.5% of the albumin alleles in hepatocytes. We established that hF9 was produced only from on-target integration, and ribosomal skipping was highly efficient. Stable hF9 plasma levels at 7–20% of normal were obtained, and treated factor IX deficient mice had normal coagulation times. In conclusion, transgene integration as a 2A-fusion to a highly expressed endogenous gene may obviate the requirement for nucleases and/or vector-borne promoters. This method may allow for safe and efficacious gene targeting in both infants and adults by greatly diminishing off-target effects while still providing therapeutic levels of expression from integration.
- Published
- 2014
34. Pulmonary macrophage transplantation therapy
- Author
-
Shuichi Abe, Cole Trapnell, Paritha Arumugam, Brenna Carey, Carolyn Lutzko, Thomas Moritz, Claudia Chalk, Takuji Suzuki, Anthony Sallese, Nico Lachmann, Takuro Sakagami, Punam Malik, Bruce C. Trapnell, and Robert E. Wood
- Subjects
Male ,Time Factors ,Cell Transplantation ,Genetic enhancement ,Cell Separation ,Pulmonary Alveolar Proteinosis ,Biology ,Article ,Cytokine Receptor Common beta Subunit ,Cell therapy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Macrophages, Alveolar ,medicine ,Animals ,Macrophage ,Lung ,Surfactant homeostasis ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Surfactant Homeostasis ,GM-CSF ,Myeloid Cell Disorder ,Gene Therapy ,Genetic Therapy ,medicine.disease ,M-CSF ,Genetic Disease ,3. Good health ,Transplantation ,Phenotype ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Alveolar macrophage ,Female ,Pulmonary alveolar proteinosis ,Alveolar Macrophage - Abstract
Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-β-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.
- Published
- 2014
35. Gene therapy: Erasing sickle-cell disease
- Author
-
Katherine Bourzac
- Subjects
0301 basic medicine ,Anemia ,Genetic enhancement ,medicine.medical_treatment ,Cell ,Hematopoietic stem cell transplantation ,Disease ,Anemia, Sickle Cell ,Bioinformatics ,Genetic therapy ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,Genome editing ,medicine ,Humans ,030212 general & internal medicine ,Gene Editing ,Clinical Trials as Topic ,Multidisciplinary ,business.industry ,fungi ,Hematopoietic Stem Cell Transplantation ,food and beverages ,Genetic Therapy ,medicine.disease ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Female ,CRISPR-Cas Systems ,business - Abstract
Clinical trials may soon test whether gene editing can cure a group of debilitating haemoglobin disorders.
- Published
- 2017
36. CRISPR fixes disease gene in viable human embryos
- Author
-
Heidi Ledford
- Subjects
0301 basic medicine ,Disease gene ,Genetics ,Gene Editing ,Multidisciplinary ,Mosaicism ,Genetic enhancement ,Embryo ,Biology ,Cardiomyopathy, Hypertrophic ,Embryo, Mammalian ,Mitochondrial Replacement Therapy ,Substrate Specificity ,03 medical and health sciences ,030104 developmental biology ,Genome editing ,CRISPR ,Substrate specificity ,Humans ,Patient Safety ,CRISPR-Cas Systems ,Carrier Proteins - Published
- 2017
37. Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells
- Author
-
Mirjam van der Burg, Giulia Schiroli, Bernhard Gentner, Angelo Lombardo, Giulia Escobar, Luigi Naldini, Michael C. Holmes, Roberta Mazzieri, Davide Moi, Chiara Bonini, Pietro Genovese, Philip D. Gregory, Claudia Firrito, Eugenio Montini, Andrea Calabria, Tiziano Di Tomaso, Immunology, Genovese, P, Schiroli, G, Escobar, G, Di Tomaso, T, Firrito, C, Calabria, A, Moi, D, Mazzieri, R, Bonini, MARIA CHIARA, Holmes, Mc, Gregory, Pd, van der Burg, M, Gentner, B, Montini, E, Lombardo, ANGELO LEONE, and Naldini, Luigi
- Subjects
Male ,DNA, Complementary ,Genetic enhancement ,Transgene ,Antigens, CD34 ,Biology ,Gene delivery ,X-Linked Combined Immunodeficiency Diseases ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Genome editing ,Animals ,Humans ,030304 developmental biology ,Genetics ,0303 health sciences ,Transcription activator-like effector nuclease ,Multidisciplinary ,Genome, Human ,Hematopoietic Stem Cell Transplantation ,Gene targeting ,Endonucleases ,Fetal Blood ,Hematopoietic Stem Cells ,Hematopoiesis ,Cell biology ,Haematopoiesis ,030220 oncology & carcinogenesis ,Mutation ,Gene Targeting ,Stem cell ,Interleukin Receptor Common gamma Subunit ,Targeted Gene Repair - Abstract
Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases.
- Published
- 2014
38. G ene-silencing technology gets first drug approval after 20-year wait
- Author
-
Heidi Ledford
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Multidisciplinary ,Drug discovery ,business.industry ,Genetic enhancement ,digestive, oral, and skin physiology ,Medical research ,Food and drug administration ,03 medical and health sciences ,030104 developmental biology ,medicine ,Drug approval ,Gene silencing ,Intensive care medicine ,business - Abstract
The US Food and Drug Administration’s decision breathes new life into RNA-interference therapies. RNA-interference therapies were once left for dead but now the US Food and Drug Administration has approved patisiran.
- Published
- 2018
39. Gene therapy in mouse fetuses treats deadly disease
- Author
-
Heidi Ledford
- Subjects
0301 basic medicine ,Fetus ,Pathology ,medicine.medical_specialty ,Multidisciplinary ,business.industry ,Genetic enhancement ,Disease ,03 medical and health sciences ,030104 developmental biology ,In utero ,medicine ,business ,reproductive and urinary physiology - Abstract
The method could minimize damage from disease if a condition is diagnosed in utero. The method could minimize damage from disease if a condition is diagnosed in utero.
- Published
- 2018
40. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model
- Author
-
Mark A. Kay, Markus Grompe, Yue Zhang, Kirk Chu, Ian E. Alexander, Sean Nygaard, Sharon C. Cunningham, Elizabeth M. Wilson, Leszek Lisowski, and Allison P Dane
- Subjects
Male ,Carcinoma, Hepatocellular ,Liver cytology ,viruses ,Transgene ,Genetic enhancement ,Genetic Vectors ,Biology ,Article ,Transduction (genetics) ,Mice ,Capsid ,Species Specificity ,In vivo ,Transduction, Genetic ,Cell Line, Tumor ,Animals ,Humans ,Transgenes ,Cells, Cultured ,Clinical Trials as Topic ,Multidisciplinary ,Chimera ,Genetic Therapy ,Dependovirus ,Virology ,In vitro ,3. Good health ,Disease Models, Animal ,Liver ,Cell culture ,Hepatocytes ,Heterografts ,Capsid Proteins ,Female - Abstract
Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome. Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human-murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes in vivo. As predicted from preclinical and clinical studies, rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly-approximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.
- Published
- 2013
41. Gene editing staves off deafness in mice
- Author
-
Heidi Ledford
- Subjects
Genetics ,Multidisciplinary ,Genome editing ,Genetic enhancement ,otorhinolaryngologic diseases ,Mutant gene ,CRISPR ,sense organs ,Biology - Abstract
Technique to knock out mutant gene relies on fatty molecules to deliver CRISPR components to inner-ear cells. Technique to knock out mutant gene relies on fatty molecules to deliver CRISPR components to inner-ear cells.
- Published
- 2017
42. Transgenic stem cells replace skin
- Author
-
Cédric Blanpain and Mariaceleste Aragona
- Subjects
0301 basic medicine ,Multidisciplinary ,integumentary system ,Epidermis (botany) ,Genetic enhancement ,Gene delivery ,Biology ,Viral vector ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Dermis ,Immunology ,medicine ,Cancer research ,Stem cell ,Junctional epidermolysis bullosa (veterinary medicine) ,Ex vivo - Abstract
The treatment of a patient affected by an incurable genetic skin disease demonstrates the efficacy, feasibility and safety of replacing almost the whole skin using genetically corrected stem cells. See Letter p.327 Patients with junctional epidermolysis bullosa (JEB) carry mutations in genes that encode components of the basement membrane, which ensures the integrity between the epidermis and the dermis, such as laminin-332. These mutations cause blistering of the skin and chronic wounds. Following initial treatment of an adult patient with a limited affected region, Michele De Luca and colleagues reconstruct the full epidermis of a 7-year-old patient with autologous transgenic cells transduced with a virus vector carrying the non-mutated form of laminin-322. The integration sites of the virus used for gene delivery provide a tracing tool ex vivo and in vivo and demonstrate that the human epidermis is sustained by a limited number of long-lived stem cells.
- Published
- 2017
43. Gene therapy: Editorial control
- Author
-
Katharine Gammon
- Subjects
Clinical Trials as Topic ,Endodeoxyribonucleases ,Multidisciplinary ,DNA Repair ,Genetic enhancement ,Anemia, Sickle Cell ,Genetic Therapy ,Computational biology ,Biology ,Hematopoietic Stem Cells ,Medical research ,Humans ,CRISPR-Cas Systems ,Genetic Engineering - Published
- 2014
44. Gene therapy: A new chapter
- Author
-
Anthony King
- Subjects
0301 basic medicine ,Multidisciplinary ,business.industry ,Genetic enhancement ,Genetic Vectors ,MEDLINE ,Genetic Therapy ,Bioinformatics ,Genetic therapy ,03 medical and health sciences ,030104 developmental biology ,Immunology ,Medicine ,Humans ,business - Abstract
In the 1980s, bone-marrow transplants transformed the lives of children with fatal lysosomal diseases. Researchers are now working on another revolutionary treatment.
- Published
- 2016
45. Gene therapy: Industrial strength
- Author
-
Eric Bender
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genetic enhancement ,Treatment outcome ,Genetic Vectors ,Herpesvirus 1, Human ,Genetic therapy ,03 medical and health sciences ,Dependovirus ,Dogs ,Rare Diseases ,Antibodies monoclonal ,Central Nervous System Diseases ,Neoplasms ,Drug approval ,Medicine ,Animals ,Humans ,Precision Medicine ,Intensive care medicine ,Drug Approval ,Clinical Trials as Topic ,Multidisciplinary ,business.industry ,Lentivirus ,Antibodies, Monoclonal ,Genetic Therapy ,Precision medicine ,Hematologic Diseases ,030104 developmental biology ,Treatment Outcome ,Immunology ,Personalized medicine ,Patient Safety ,business - Abstract
After a series of setbacks, genetic therapies are finally moving beyond small academic trials towards approval as treatments.
- Published
- 2016
46. In vivo genome editing restores haemostasis in a mouse model of haemophilia
- Author
-
Xavier M. Anguela, Yannick Doyon, Rajiv Sharma, Sunnie Wong, Fayaz R. Khazi, Edward J. Rebar, Virginia Haurigot, Anand S. Bhagwat, Hojun Li, Nirav Malani, Tianjian Li, Michael C. Holmes, Philip D. Gregory, Samuel L. Murphy, Jonathan D. Finn, Shangzhen Zhou, Katherine A. High, Lacramiora Ivanciu, Frederic D. Bushman, and David Paschon
- Subjects
DNA Repair ,Genetic enhancement ,Genetic Vectors ,Sequence Homology ,Computational biology ,Biology ,Hemophilia B ,Genome ,Article ,Factor IX ,Mice ,Genome editing ,Cell Line, Tumor ,Animals ,Humans ,DNA Breaks, Double-Stranded ,Gene ,Genetics ,Hemostasis ,Multidisciplinary ,Base Sequence ,fungi ,Genetic transfer ,Gene targeting ,Zinc Fingers ,Exons ,Genetic Therapy ,Endonucleases ,Zinc finger nuclease ,Introns ,Liver Regeneration ,Mice, Inbred C57BL ,Disease Models, Animal ,HEK293 Cells ,Phenotype ,Liver ,Gene Targeting ,Mutation ,Human genome - Abstract
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation 1 . In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus 2–4 , but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homologyindependent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFNdriven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.
- Published
- 2011
47. FDA advisers back gene therapy for rare form of blindness
- Author
-
Heidi Ledford
- Subjects
0301 basic medicine ,03 medical and health sciences ,Pediatrics ,medicine.medical_specialty ,030104 developmental biology ,Multidisciplinary ,Blindness ,business.industry ,Genetic enhancement ,medicine ,medicine.disease ,business - Abstract
Therapy that targets disease-causing mutations could become the first of its kind approved for use in the United States.
- Published
- 2017
48. An essential receptor for adeno-associated virus infection
- Author
-
Jonathan E. Wosen, Michael Chapman, Jonathan Diep, Yoshihiro Ishikawa, Jan E. Carette, Claude M. Nagamine, Lucas T. Jae, Nancy L. Meyer, Sirika Pillay, Andreas S. Puschnik, and Omar Davulcu
- Subjects
0301 basic medicine ,Male ,Virus genetics ,viruses ,Genetic enhancement ,Receptors, Cell Surface ,Gene delivery ,Biology ,medicine.disease_cause ,Virus ,Antibodies ,Host Specificity ,Cell Line ,Parvoviridae Infections ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Adeno-associated virus ,Host factor ,Multidisciplinary ,Genetic Therapy ,Dependovirus ,Virus Internalization ,Virology ,Endocytosis ,3. Good health ,Viral Tropism ,030104 developmental biology ,Tissue tropism ,Receptors, Virus ,Female ,030217 neurology & neurosurgery ,Gene Deletion ,Genetic screen ,trans-Golgi Network - Abstract
Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.
- Published
- 2015
49. Gene therapy: Genie in a vector
- Author
-
Julie Gould
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Multidisciplinary ,Factor VIII ,business.industry ,Genetic enhancement ,Genetic Vectors ,Cell- and Tissue-Based Therapy ,Disease ,Computational biology ,Genetic Therapy ,Dependovirus ,Bioinformatics ,Haemophilia ,medicine.disease ,Hemophilia A ,Hemophilia B ,Factor IX ,hemic and lymphatic diseases ,Medicine ,Animals ,Humans ,Vector (molecular biology) ,business ,Gene - Abstract
Repairing the faulty genes that cause haemophilia could ultimately cure the disease, but it will be a tough challenge.
- Published
- 2014
50. Primed for take-off
- Author
-
Philippe Leboulch
- Subjects
Multidisciplinary ,business.industry ,Genetic enhancement ,Bumper crop ,Potency ,Medicine ,Clinical efficacy ,Pharmacology ,Bioinformatics ,business - Abstract
Gene therapy is finally getting a bumper crop of data that show clinical efficacy after fine-tuning of key parameters that control safety and potency. Supporting evidence comes from treatment of two life-threatening human diseases.
- Published
- 2013
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