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Simon N. Waddington
MRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg 2193, South Africa

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Journal article
Published: 28 July 2021 in Viruses
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The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

ACS Style

Emily Bates; John Counsell; Sophie Alizert; Alexander Baker; Natalie Suff; Ashley Boyle; Angela Bradshaw; Simon Waddington; Stuart Nicklin; Andrew Baker; Alan Parker. In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications. Viruses 2021, 13, 1483 .

AMA Style

Emily Bates, John Counsell, Sophie Alizert, Alexander Baker, Natalie Suff, Ashley Boyle, Angela Bradshaw, Simon Waddington, Stuart Nicklin, Andrew Baker, Alan Parker. In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications. Viruses. 2021; 13 (8):1483.

Chicago/Turabian Style

Emily Bates; John Counsell; Sophie Alizert; Alexander Baker; Natalie Suff; Ashley Boyle; Angela Bradshaw; Simon Waddington; Stuart Nicklin; Andrew Baker; Alan Parker. 2021. "In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications." Viruses 13, no. 8: 1483.

Preprint
Published: 22 July 2021
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The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of preexisting immunity detected across screened populations. However, many aspects of the basic virology of species D, such as their cellular tropism, receptor usage and in vivo biodistribution profile, remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49), a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen whilst avoiding liver interactions, such as intravascular vaccine applications.

ACS Style

Emily A. Bates; John R. Counsell; Sophie Alizert; Alexander T. Baker; Natalie Suff; Ashley Boyle; Angela C. Bradshaw; Simon N. Waddington; Stuart A. Nicklin; Andrew H. Baker; Alan L. Parker. In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications. 2021, 1 .

AMA Style

Emily A. Bates, John R. Counsell, Sophie Alizert, Alexander T. Baker, Natalie Suff, Ashley Boyle, Angela C. Bradshaw, Simon N. Waddington, Stuart A. Nicklin, Andrew H. Baker, Alan L. Parker. In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications. . 2021; ():1.

Chicago/Turabian Style

Emily A. Bates; John R. Counsell; Sophie Alizert; Alexander T. Baker; Natalie Suff; Ashley Boyle; Angela C. Bradshaw; Simon N. Waddington; Stuart A. Nicklin; Andrew H. Baker; Alan L. Parker. 2021. "In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications." , no. : 1.

Research article
Published: 19 May 2021 in Science Translational Medicine
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Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

ACS Style

Joanne Ng; Serena Barral; Carmen De La Fuente Barrigon; Gabriele Lignani; Fatma A. Erdem; Rebecca Wallings; Riccardo Privolizzi; Giada Rossignoli; Haya Alrashidi; Sonja Heasman; Esther Meyer; Adeline Ngoh; Simon Pope; Rajvinder Karda; Dany Perocheau; Julien Baruteau; Natalie Suff; Juan Antinao Diaz; Stephanie Schorge; Jane Vowles; Lucy R. Marshall; Sally A. Cowley; Sonja Sucic; Michael Freissmuth; John R. Counsell; Richard Wade-Martins; Simon J. R. Heales; Ahad A. Rahim; Maximilien Bencze; Simon N. Waddington; Manju A. Kurian. Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism. Science Translational Medicine 2021, 13, eaaw1564 .

AMA Style

Joanne Ng, Serena Barral, Carmen De La Fuente Barrigon, Gabriele Lignani, Fatma A. Erdem, Rebecca Wallings, Riccardo Privolizzi, Giada Rossignoli, Haya Alrashidi, Sonja Heasman, Esther Meyer, Adeline Ngoh, Simon Pope, Rajvinder Karda, Dany Perocheau, Julien Baruteau, Natalie Suff, Juan Antinao Diaz, Stephanie Schorge, Jane Vowles, Lucy R. Marshall, Sally A. Cowley, Sonja Sucic, Michael Freissmuth, John R. Counsell, Richard Wade-Martins, Simon J. R. Heales, Ahad A. Rahim, Maximilien Bencze, Simon N. Waddington, Manju A. Kurian. Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism. Science Translational Medicine. 2021; 13 (594):eaaw1564.

Chicago/Turabian Style

Joanne Ng; Serena Barral; Carmen De La Fuente Barrigon; Gabriele Lignani; Fatma A. Erdem; Rebecca Wallings; Riccardo Privolizzi; Giada Rossignoli; Haya Alrashidi; Sonja Heasman; Esther Meyer; Adeline Ngoh; Simon Pope; Rajvinder Karda; Dany Perocheau; Julien Baruteau; Natalie Suff; Juan Antinao Diaz; Stephanie Schorge; Jane Vowles; Lucy R. Marshall; Sally A. Cowley; Sonja Sucic; Michael Freissmuth; John R. Counsell; Richard Wade-Martins; Simon J. R. Heales; Ahad A. Rahim; Maximilien Bencze; Simon N. Waddington; Manju A. Kurian. 2021. "Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism." Science Translational Medicine 13, no. 594: eaaw1564.

Review
Published: 20 April 2021 in Biomolecules
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Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years.

ACS Style

Giulia Massaro; Amy Geard; Wenfei Liu; Oliver Coombe-Tennant; Simon Waddington; Julien Baruteau; Paul Gissen; Ahad Rahim. Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development. Biomolecules 2021, 11, 611 .

AMA Style

Giulia Massaro, Amy Geard, Wenfei Liu, Oliver Coombe-Tennant, Simon Waddington, Julien Baruteau, Paul Gissen, Ahad Rahim. Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development. Biomolecules. 2021; 11 (4):611.

Chicago/Turabian Style

Giulia Massaro; Amy Geard; Wenfei Liu; Oliver Coombe-Tennant; Simon Waddington; Julien Baruteau; Paul Gissen; Ahad Rahim. 2021. "Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development." Biomolecules 11, no. 4: 611.

Journal article
Published: 09 October 2020 in F1000Research
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Bioluminescence imaging enables noninvasive quantification of luciferase reporter gene expression in transgenic tissues of living rodents. Luciferase transgene expression can be regulated by endogenous gene promoters after targeted knock-in of the reporter gene, usually within the first intron of the gene. Even using CRISPR/Cas9 mediated genome editing this can be a time consuming and costly process. The generation of germline transgenic (GLT) rodents by targeted genomic integration of a gene expression cassette in embryonic stem (ES) cells is commonplace but results in the wastage of large numbers of animals during colony generation, back-crossing and maintenance. Using a synthetic/truncated promoter-driven luciferase gene to study promoter activity in a given tissue or organ of a GLT also often results in unwanted background luciferase activity during whole-body bioluminescent imaging as every cell contains the reporter. We have developed somatotransgenic bioimaging; a method to generate tissue-restricted transcription factor activated luciferase reporter (TFAR) cassettes in rodents that substantially reduces the number of animals required for experimentation. Bespoke designed TFARs are delivered to newborn pups using viral vectors targeted to specific organs by tissue-tropic pseudotypes. Retention and proliferation of TFARs is facilitated by stem/progenitor cell transduction and immune tolerance to luciferase due to the naïve neonatal immune system. We have successfully applied both lentiviral and adeno-associated virus (AAV) vectors in longitudinal rodent studies, targeting TFARs to the liver and brain during normal development and in well-established disease models. Development of somatotransgenic animals has broad applicability to non-invasively determine mechanistic insights into homeostatic and disease states and assess toxicology and efficacy testing. Somatotransgenic bioimaging technology is superior to current whole-body, light-emitting transgenic models as it reduces the numbers of animals used by generating only the required number of animals. It is also a refinement over current technologies given the ability to use conscious, unrestrained animals.

ACS Style

Juliette M. Delhove; Rajvinder Karda; Lorna M. Fitzpatrick; Suzanne M.K. Buckley; Simon N. Waddington; Tristan R. McKay. Non-invasive somatotransgenic bioimaging in living animals. F1000Research 2020, 9, 1216 .

AMA Style

Juliette M. Delhove, Rajvinder Karda, Lorna M. Fitzpatrick, Suzanne M.K. Buckley, Simon N. Waddington, Tristan R. McKay. Non-invasive somatotransgenic bioimaging in living animals. F1000Research. 2020; 9 ():1216.

Chicago/Turabian Style

Juliette M. Delhove; Rajvinder Karda; Lorna M. Fitzpatrick; Suzanne M.K. Buckley; Simon N. Waddington; Tristan R. McKay. 2020. "Non-invasive somatotransgenic bioimaging in living animals." F1000Research 9, no. : 1216.

Preprint content
Published: 24 July 2020
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Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.

ACS Style

Leandro R. Soria; Dany P Perocheau; Giulia De Sabbata; Angela De Angelis; Gemma Bruno; Elena Polishchuk; Sonam Gurung; Debora Paris; Paola Cuomo; Andrea Motta; Michael Orford; Simon Eaton; Simon Waddington; Carmine Settembre; Andres F Muro; Julien Baruteau; Nicola Brunetti-Pierri. Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders. 2020, 1 .

AMA Style

Leandro R. Soria, Dany P Perocheau, Giulia De Sabbata, Angela De Angelis, Gemma Bruno, Elena Polishchuk, Sonam Gurung, Debora Paris, Paola Cuomo, Andrea Motta, Michael Orford, Simon Eaton, Simon Waddington, Carmine Settembre, Andres F Muro, Julien Baruteau, Nicola Brunetti-Pierri. Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders. . 2020; ():1.

Chicago/Turabian Style

Leandro R. Soria; Dany P Perocheau; Giulia De Sabbata; Angela De Angelis; Gemma Bruno; Elena Polishchuk; Sonam Gurung; Debora Paris; Paola Cuomo; Andrea Motta; Michael Orford; Simon Eaton; Simon Waddington; Carmine Settembre; Andres F Muro; Julien Baruteau; Nicola Brunetti-Pierri. 2020. "Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders." , no. : 1.

Correction
Published: 09 March 2020 in Cell Death & Differentiation
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ACS Style

Nicoletta Plotegher; Dany Perocheau; Ruggero Ferrazza; Giulia Massaro; Gauri Bhosale; Federico Zambon; Ahad A. Rahim; Graziano Guella; Simon N. Waddington; Gyorgy Szabadkai; Michael R. Duchen. Correction: Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death & Differentiation 2020, 27, 2534 -2534.

AMA Style

Nicoletta Plotegher, Dany Perocheau, Ruggero Ferrazza, Giulia Massaro, Gauri Bhosale, Federico Zambon, Ahad A. Rahim, Graziano Guella, Simon N. Waddington, Gyorgy Szabadkai, Michael R. Duchen. Correction: Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death & Differentiation. 2020; 27 (8):2534-2534.

Chicago/Turabian Style

Nicoletta Plotegher; Dany Perocheau; Ruggero Ferrazza; Giulia Massaro; Gauri Bhosale; Federico Zambon; Ahad A. Rahim; Graziano Guella; Simon N. Waddington; Gyorgy Szabadkai; Michael R. Duchen. 2020. "Correction: Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload." Cell Death & Differentiation 27, no. 8: 2534-2534.

Journal article
Published: 07 February 2020 in Scientific Reports
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We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation. An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days. We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner in a model of LPS-induced inflammation. This technology complements existing germline-transgenic models and may be applicable to other rodent disease models.

ACS Style

Rajvinder Karda; Ahad Rahim; Andrew M. S. Wong; Natalie Suff; Juan Antinao Diaz; Dany P. Perocheau; Maha Tijani; Joanne Ng; Julien Baruteau; Nuria Palomar Martin; Michael Hughes; Juliette M. K. M. Delhove; John R. Counsell; Jonathan D. Cooper; Els Jeanny V Henckaerts; Tristan R. McKay; Suzanne M. K. Buckley; Simon N. Waddington. Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors. Scientific Reports 2020, 10, 2121 -9.

AMA Style

Rajvinder Karda, Ahad Rahim, Andrew M. S. Wong, Natalie Suff, Juan Antinao Diaz, Dany P. Perocheau, Maha Tijani, Joanne Ng, Julien Baruteau, Nuria Palomar Martin, Michael Hughes, Juliette M. K. M. Delhove, John R. Counsell, Jonathan D. Cooper, Els Jeanny V Henckaerts, Tristan R. McKay, Suzanne M. K. Buckley, Simon N. Waddington. Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors. Scientific Reports. 2020; 10 (1):2121-9.

Chicago/Turabian Style

Rajvinder Karda; Ahad Rahim; Andrew M. S. Wong; Natalie Suff; Juan Antinao Diaz; Dany P. Perocheau; Maha Tijani; Joanne Ng; Julien Baruteau; Nuria Palomar Martin; Michael Hughes; Juliette M. K. M. Delhove; John R. Counsell; Jonathan D. Cooper; Els Jeanny V Henckaerts; Tristan R. McKay; Suzanne M. K. Buckley; Simon N. Waddington. 2020. "Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors." Scientific Reports 10, no. 1: 2121-9.

Journal article
Published: 10 January 2020 in Human Molecular Genetics
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Gaucher disease is caused by mutations in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (GCase), resulting in the accumulation of storage material in visceral organs and in some cases the brain of affected patients. While there is a commercially available treatment for the systemic manifestations, neuropathology still remains untreatable. We previously demonstrated that gene therapy represents a feasible therapeutic tool for the treatment of the neuronopathic forms of Gaucher disease (nGD). In order to further enhance the therapeutic affects to the central nervous system, we systemically delivered an adeno-associated virus (AAV) serotype 9 carrying the human GBA gene under control of a neuron-specific promoter to an nGD mouse model. Gene therapy increased the life span of treated animals, rescued the lethal neurodegeneration, normalized the locomotor behavioural defects and ameliorated the visceral pathology. Together, these results provided further indication of gene therapy as a possible effective treatment option for the neuropathic forms of Gaucher disease.

ACS Style

Giulia Massaro; Michael P Hughes; Sammie M Whaler; Kerri-Lee Wallom; David A Priestman; Frances Platt; Simon N Waddington; Ahad A Rahim. Systemic AAV9 gene therapy using the synapsin I promoter rescues a mouse model of neuronopathic Gaucher disease but with limited cross-correction potential to astrocytes. Human Molecular Genetics 2020, 29, 1933 -1949.

AMA Style

Giulia Massaro, Michael P Hughes, Sammie M Whaler, Kerri-Lee Wallom, David A Priestman, Frances Platt, Simon N Waddington, Ahad A Rahim. Systemic AAV9 gene therapy using the synapsin I promoter rescues a mouse model of neuronopathic Gaucher disease but with limited cross-correction potential to astrocytes. Human Molecular Genetics. 2020; 29 (12):1933-1949.

Chicago/Turabian Style

Giulia Massaro; Michael P Hughes; Sammie M Whaler; Kerri-Lee Wallom; David A Priestman; Frances Platt; Simon N Waddington; Ahad A Rahim. 2020. "Systemic AAV9 gene therapy using the synapsin I promoter rescues a mouse model of neuronopathic Gaucher disease but with limited cross-correction potential to astrocytes." Human Molecular Genetics 29, no. 12: 1933-1949.

Publisher correction
Published: 24 December 2019 in Scientific Reports
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ACS Style

Panicos Shangaris; Stavros P. Loukogeorgakis; Sindhu Subramaniam; Christina Flouri; Laurence H. Jackson; Wei Wang; Michael Blundell; Shanrun Liu; Simon Eaton; Nahla Bakhamis; Durrgah Latchumi Ramachandra; Panagiotis Maghsoudlou; Luca Urbani; Simon N. Waddington; Ayad Eddaoudi; Joy Archer; Michael N. Antoniou; Daniel Stuckey; Manfred Schmidt; Adrian J. Thrasher; Thomas M. Ryan; Paolo De Coppi; Anna L. David. Publisher Correction: In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Scientific Reports 2019, 9, 1 -1.

AMA Style

Panicos Shangaris, Stavros P. Loukogeorgakis, Sindhu Subramaniam, Christina Flouri, Laurence H. Jackson, Wei Wang, Michael Blundell, Shanrun Liu, Simon Eaton, Nahla Bakhamis, Durrgah Latchumi Ramachandra, Panagiotis Maghsoudlou, Luca Urbani, Simon N. Waddington, Ayad Eddaoudi, Joy Archer, Michael N. Antoniou, Daniel Stuckey, Manfred Schmidt, Adrian J. Thrasher, Thomas M. Ryan, Paolo De Coppi, Anna L. David. Publisher Correction: In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Scientific Reports. 2019; 9 (1):1-1.

Chicago/Turabian Style

Panicos Shangaris; Stavros P. Loukogeorgakis; Sindhu Subramaniam; Christina Flouri; Laurence H. Jackson; Wei Wang; Michael Blundell; Shanrun Liu; Simon Eaton; Nahla Bakhamis; Durrgah Latchumi Ramachandra; Panagiotis Maghsoudlou; Luca Urbani; Simon N. Waddington; Ayad Eddaoudi; Joy Archer; Michael N. Antoniou; Daniel Stuckey; Manfred Schmidt; Adrian J. Thrasher; Thomas M. Ryan; Paolo De Coppi; Anna L. David. 2019. "Publisher Correction: In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques." Scientific Reports 9, no. 1: 1-1.

Journal article
Published: 12 November 2019 in Metabolites
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Background: Dried bloodspots are easy to collect and to transport to assess various metabolites, such as amino acids. Dried bloodspots are routinely used for diagnosis and monitoring of some inherited metabolic diseases. Methods: Measurement of amino acids from dried blood spots by liquid chromatography-tandem mass spectrometry. Results: We describe a novel rapid method to measure underivatised urea cycle related amino acids. Application of this method enabled accurate monitoring of these amino acids to assess the efficacy of therapies in argininosuccinate lyase deficient mice and monitoring of these metabolites in patients with urea cycle defects. Conclusion: Measuring urea cycle related amino acids in urea cycle defects from dried blood spots is a reliable tool in animal research and will be of benefit in the clinic, facilitating optimisation of protein-restricted diet and preventing amino acid deprivation.

ACS Style

Julien Baruteau; Youssef Khalil; Stephanie Grunewald; Marta Zancolli; Anupam Chakrapani; Maureen Cleary; James Davison; Emma Footitt; Simon N. Waddington; Paul Gissen; Philippa Mills. Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment. Metabolites 2019, 9, 275 .

AMA Style

Julien Baruteau, Youssef Khalil, Stephanie Grunewald, Marta Zancolli, Anupam Chakrapani, Maureen Cleary, James Davison, Emma Footitt, Simon N. Waddington, Paul Gissen, Philippa Mills. Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment. Metabolites. 2019; 9 (11):275.

Chicago/Turabian Style

Julien Baruteau; Youssef Khalil; Stephanie Grunewald; Marta Zancolli; Anupam Chakrapani; Maureen Cleary; James Davison; Emma Footitt; Simon N. Waddington; Paul Gissen; Philippa Mills. 2019. "Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment." Metabolites 9, no. 11: 275.

Journal article
Published: 04 November 2019 in Cell Death & Differentiation
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Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson’s disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1 −/− ) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca2+]c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca2+ uptake was reduced in gba1 −/− cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1 −/− neurons. Behavior of gba1 +/− neurons was similar to gba1 −/− in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca2+]c dysregulation as mechanisms driving neurodegeneration.

ACS Style

Nicoletta Plotegher; Dany Perocheau; Ruggero Ferrazza; Giulia Massaro; Gauri Bhosale; Federico Zambon; Ahad A. Rahim; Graziano Guella; Simon N. Waddington; Gyorgy Szabadkai; Michael R. Duchen. Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death & Differentiation 2019, 27, 1588 -1603.

AMA Style

Nicoletta Plotegher, Dany Perocheau, Ruggero Ferrazza, Giulia Massaro, Gauri Bhosale, Federico Zambon, Ahad A. Rahim, Graziano Guella, Simon N. Waddington, Gyorgy Szabadkai, Michael R. Duchen. Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death & Differentiation. 2019; 27 (5):1588-1603.

Chicago/Turabian Style

Nicoletta Plotegher; Dany Perocheau; Ruggero Ferrazza; Giulia Massaro; Gauri Bhosale; Federico Zambon; Ahad A. Rahim; Graziano Guella; Simon N. Waddington; Gyorgy Szabadkai; Michael R. Duchen. 2019. "Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload." Cell Death & Differentiation 27, no. 5: 1588-1603.

Journal article
Published: 12 August 2019 in Scientific Reports
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In utero gene therapy (IUGT) to the fetal hematopoietic compartment could be used to treat congenital blood disorders such as β-thalassemia. A humanised mouse model of β-thalassemia was used, in which heterozygous animals are anaemic with splenomegaly and extramedullary hematopoiesis. Intrahepatic in utero injections of a β globin-expressing lentiviral vector (GLOBE), were performed in fetuses at E13.5 of gestation. We analysed animals at 12 and 32 weeks of age, for vector copy number in bone marrow, peripheral blood liver and spleen and we performed integration site analysis. Compared to noninjected heterozygous animals IUGT normalised blood haemoglobin levels and spleen weight. Integration site analysis showed polyclonality. The left ventricular ejection fraction measured using magnetic resonance imaging (MRI) in treated heterozygous animals was similar to that of normal non-β-thalassemic mice but significantly higher than untreated heterozygous thalassemia mice suggesting that IUGT ameliorated poor cardiac function. GLOBE LV-mediated IUGT normalised the haematological and anatomical phenotype in a heterozygous humanised model of β-thalassemia.

ACS Style

Panicos Shangaris; Stavros P. Loukogeorgakis; Sindhu Subramaniam; Christina Flouri; Laurence H. Jackson; Wei Wang; Michael Blundell; Shanrun Liu; Simon Eaton; Nahla Bakhamis; Durrgah Latchumi Ramachandra; Panagiotis Maghsoudlou; Luca Urbani; Simon N. Waddington; Ayad Eddaoudi; Joy Archer; Michael N. Antoniou; Daniel Stuckey; Manfred Schmidt; Adrian J. Thrasher; Thomas Ryan; Paolo De Coppi; Anna L. David. In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Scientific Reports 2019, 9, 1 -17.

AMA Style

Panicos Shangaris, Stavros P. Loukogeorgakis, Sindhu Subramaniam, Christina Flouri, Laurence H. Jackson, Wei Wang, Michael Blundell, Shanrun Liu, Simon Eaton, Nahla Bakhamis, Durrgah Latchumi Ramachandra, Panagiotis Maghsoudlou, Luca Urbani, Simon N. Waddington, Ayad Eddaoudi, Joy Archer, Michael N. Antoniou, Daniel Stuckey, Manfred Schmidt, Adrian J. Thrasher, Thomas Ryan, Paolo De Coppi, Anna L. David. In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Scientific Reports. 2019; 9 (1):1-17.

Chicago/Turabian Style

Panicos Shangaris; Stavros P. Loukogeorgakis; Sindhu Subramaniam; Christina Flouri; Laurence H. Jackson; Wei Wang; Michael Blundell; Shanrun Liu; Simon Eaton; Nahla Bakhamis; Durrgah Latchumi Ramachandra; Panagiotis Maghsoudlou; Luca Urbani; Simon N. Waddington; Ayad Eddaoudi; Joy Archer; Michael N. Antoniou; Daniel Stuckey; Manfred Schmidt; Adrian J. Thrasher; Thomas Ryan; Paolo De Coppi; Anna L. David. 2019. "In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques." Scientific Reports 9, no. 1: 1-17.

Preprint
Published: 20 May 2019
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Approximately 40% of preterm births are preceded by microbial invasion of the intrauterine space: ascent from the vagina is the most common pathway. Within the cervical canal, antimicrobial peptides and proteins (AMPs) help to constitute a barrier which prevents ascending infection. We investigated whether expression of the AMP, human β-defensin-3 (HBD3), in the cervical mucosa prevented bacterial ascent from the vagina into the uterine cavity of pregnant mice. An adeno-associated virus vector containing both the HBD3 gene and GFP transgene (AAV8 HBD3.GFP) or control (AAV8 GFP), was administered intravaginally into E13.5 pregnant mice. Ascending infection was induced at E16.5 using bioluminescent E.coli (E.coli K1 A192PP-lux2). Bioluminescence imaging showed bacterial ascent into the uterine cavity, cellular events that led to premature delivery and a reduction in pups born alive, compared with uninfected controls. In addition, a significant reduction in uterine bioluminescence in the AAV8 HBD3.GFP-treated mice was observed 24 hours post-E.coli infection, compared to AAV8 GFP treated mice, signifying reduced bacterial ascent in AAV8 HBD3.GFP-treated mice. There was also an increase in the number of living pups in AAV HBD3.GFP-treated mice. We propose that HBD3 may be considered a possible candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth.

ACS Style

Natalie Suff; Rajvinder Karda; Juan Antinao Diaz; Joanne Ng; Julien Baruteau; Dany Perocheau; Peter W. Taylor; Dagmar Alber; Suzanne M.K. Buckley; Mona Bajaj-Elliott; Simon N. Waddington; Donald Peebles; Ng Joanne; Baruteau Julian. Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth. 2019, 643171 .

AMA Style

Natalie Suff, Rajvinder Karda, Juan Antinao Diaz, Joanne Ng, Julien Baruteau, Dany Perocheau, Peter W. Taylor, Dagmar Alber, Suzanne M.K. Buckley, Mona Bajaj-Elliott, Simon N. Waddington, Donald Peebles, Ng Joanne, Baruteau Julian. Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth. . 2019; ():643171.

Chicago/Turabian Style

Natalie Suff; Rajvinder Karda; Juan Antinao Diaz; Joanne Ng; Julien Baruteau; Dany Perocheau; Peter W. Taylor; Dagmar Alber; Suzanne M.K. Buckley; Mona Bajaj-Elliott; Simon N. Waddington; Donald Peebles; Ng Joanne; Baruteau Julian. 2019. "Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth." , no. : 643171.

Journal article
Published: 01 January 2019 in Human Gene Therapy
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Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. Novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. We therefore assessed the seroprevalence of antibodies against a novel synthetic liver-tropic capsid AAV-LK03. We measured seroprevalence of immunoglobulin (Ig)G (i.e., neutralizing and nonneutralizing) antibodies and Nab to AAV-LK03 in a cohort of 323 UK patients (including 260 pediatric) and 52 juvenile rhesus macaques. We also performed comparative analysis of seroprevalence of Nab against wild-type AAV8 and AAV3B capsids. Overall IgG seroprevalence for AAV-LK03 was 39% in human samples. The titer increased with age. Prevalence of Nab was 23%, 35%, and 18% for AAV-LK03, AAV3B, and AAV8, respectively, with the lowest seroprevalence between 3 and 17 years of age for all serotypes. Presence of Nab against AAV-LK03 decreased from 36% in the youngest cohort (birth to 6 months) to 7% in older primary school-age children (9–11 years) and then progressively increased to 54% in late adulthood. Cross-reactivity between serotypes was >60%. Nab seroprevalence in macaques was 62%, 85%, and 40% for AAV-LK03, AAV3B, and AAV8, respectively. When planning for AAV gene therapy clinical trials, knowing the seropositivity of the target population is critical. In the population studied, AAV seroprevalence for AAV serotypes tested was low. However, high cross-reactivity between AAV serotypes remains a barrier for re-injection. Shifts in Nab seroprevalence during the first decade need to be confirmed by longitudinal studies. This possibility suggests that pediatric patients could respond differently to AAV therapy according to age. If late childhood is an ideal age window, intervention at an early age when maternal Nab levels are high may be challenging. Nab-positive children excluded from trials could be rescreened for eligibility at regular intervals because this status may change.

ACS Style

Dany P. Perocheau; Sharon C. Cunningham; Juhee Lee; Juan Antinao Diaz; Simon Waddington; Kimberly Gilmour; Simon Eaglestone; Leszek Lisowski; Adrian Thrasher; Ian E Alexander; Paul Gissen; Julien Baruteau. Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort. Human Gene Therapy 2019, 30, 79 -87.

AMA Style

Dany P. Perocheau, Sharon C. Cunningham, Juhee Lee, Juan Antinao Diaz, Simon Waddington, Kimberly Gilmour, Simon Eaglestone, Leszek Lisowski, Adrian Thrasher, Ian E Alexander, Paul Gissen, Julien Baruteau. Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort. Human Gene Therapy. 2019; 30 (1):79-87.

Chicago/Turabian Style

Dany P. Perocheau; Sharon C. Cunningham; Juhee Lee; Juan Antinao Diaz; Simon Waddington; Kimberly Gilmour; Simon Eaglestone; Leszek Lisowski; Adrian Thrasher; Ian E Alexander; Paul Gissen; Julien Baruteau. 2019. "Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort." Human Gene Therapy 30, no. 1: 79-87.

Journal article
Published: 29 August 2018 in Nature Communications
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Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases.

ACS Style

Julien Baruteau; Dany P. Perocheau; Joanna Hanley; Maëlle Lorvellec; Eridan Rocha-Ferreira; Rajvinder Karda; Joanne Ng; Natalie Suff; Juan Antinao Diaz; Ahad A. Rahim; Michael Hughes; Blerida Banushi; Helen Prunty; Mariya Hristova; Deborah A. Ridout; Alex Virasami; Simon Heales; Stewen J. Howe; Suzanne M. K. Buckley; Philippa Mills; Paul Gissen; Simon N. Waddington. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. Nature Communications 2018, 9, 3505 .

AMA Style

Julien Baruteau, Dany P. Perocheau, Joanna Hanley, Maëlle Lorvellec, Eridan Rocha-Ferreira, Rajvinder Karda, Joanne Ng, Natalie Suff, Juan Antinao Diaz, Ahad A. Rahim, Michael Hughes, Blerida Banushi, Helen Prunty, Mariya Hristova, Deborah A. Ridout, Alex Virasami, Simon Heales, Stewen J. Howe, Suzanne M. K. Buckley, Philippa Mills, Paul Gissen, Simon N. Waddington. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. Nature Communications. 2018; 9 (1):3505.

Chicago/Turabian Style

Julien Baruteau; Dany P. Perocheau; Joanna Hanley; Maëlle Lorvellec; Eridan Rocha-Ferreira; Rajvinder Karda; Joanne Ng; Natalie Suff; Juan Antinao Diaz; Ahad A. Rahim; Michael Hughes; Blerida Banushi; Helen Prunty; Mariya Hristova; Deborah A. Ridout; Alex Virasami; Simon Heales; Stewen J. Howe; Suzanne M. K. Buckley; Philippa Mills; Paul Gissen; Simon N. Waddington. 2018. "Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer." Nature Communications 9, no. 1: 3505.

Regular article animal models
Published: 20 July 2018 in The American Journal of Pathology
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Preterm birth is a serious global health problem and the leading cause of infant death before 5 years of age. At least 40% of cases are associated with infection. The most common way for pathogens to access the uterine cavity is by ascending from the vagina. Bioluminescent pathogens have revolutionized the understanding of infectious diseases. We hypothesized that bioluminescent Escherichia coli can be used to track and monitor ascending vaginal infections. Two bioluminescent strains were studied: E. coli K12 MG1655-lux, a nonpathogenic laboratory strain, and E. coli K1 A192PP-lux2, a pathogenic strain capable of causing neonatal meningitis and sepsis in neonatal rats. On embryonic day 16, mice received intravaginal E. coli K12, E. coli K1, or phosphate-buffered saline followed by whole-body bioluminescent imaging. In both cases, intravaginal delivery of E. coli K12 or E. coli K1 led to bacterial ascension into the uterine cavity, but only E. coli K1 induced preterm parturition. Intravaginal administration of E. coli K1 significantly reduced the proportion of pups born alive compared with E. coli K12 and phosphate-buffered saline controls. However, in both groups of viable pups born after bacterial inoculation, there was evidence of comparable brain inflammation by postnatal day 6. This study ascribes specific mechanisms by which exposure to intrauterine bacteria leads to premature delivery and neurologic inflammation in neonates.

ACS Style

Natalie Suff; Rajvinder Karda; Juan A. Diaz; Joanne Ng; Julien Baruteau; Dany Perocheau; Mark Tangney; Peter W. Taylor; Donald Peebles; Suzanne M.K. Buckley; Simon N. Waddington. Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice. The American Journal of Pathology 2018, 188, 2164 -2176.

AMA Style

Natalie Suff, Rajvinder Karda, Juan A. Diaz, Joanne Ng, Julien Baruteau, Dany Perocheau, Mark Tangney, Peter W. Taylor, Donald Peebles, Suzanne M.K. Buckley, Simon N. Waddington. Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice. The American Journal of Pathology. 2018; 188 (10):2164-2176.

Chicago/Turabian Style

Natalie Suff; Rajvinder Karda; Juan A. Diaz; Joanne Ng; Julien Baruteau; Dany Perocheau; Mark Tangney; Peter W. Taylor; Donald Peebles; Suzanne M.K. Buckley; Simon N. Waddington. 2018. "Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice." The American Journal of Pathology 188, no. 10: 2164-2176.

Letter
Published: 16 July 2018 in Nature Medicine
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For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains. In utero GBA gene therapy extends lifespan and provides long-lasting phenotypic amelioration in a mouse model of neuronopathic Gaucher disease. Fetal ultrasound-guided in utero gene vector delivery is also achieved in the non-human primate brain.

ACS Style

Giulia Massaro; Citra N. Z. Mattar; Andrew M. S. Wong; Ernestas Sirka; Suzanne M. K. Buckley; Bronwen R. Herbert; Stefan Karlsson; Dany P. Perocheau; Derek Burke; Simon Heales; Angela Richard-Londt; Sebastian Brandner; Mylene Huebecker; David A. Priestman; Frances Platt; Kevin Mills; Arijit Biswas; Jonathan Cooper; Jerry K. Y. Chan; Seng H. Cheng; Simon N. Waddington; Ahad A. Rahim. Fetal gene therapy for neurodegenerative disease of infants. Nature Medicine 2018, 24, 1317 -1323.

AMA Style

Giulia Massaro, Citra N. Z. Mattar, Andrew M. S. Wong, Ernestas Sirka, Suzanne M. K. Buckley, Bronwen R. Herbert, Stefan Karlsson, Dany P. Perocheau, Derek Burke, Simon Heales, Angela Richard-Londt, Sebastian Brandner, Mylene Huebecker, David A. Priestman, Frances Platt, Kevin Mills, Arijit Biswas, Jonathan Cooper, Jerry K. Y. Chan, Seng H. Cheng, Simon N. Waddington, Ahad A. Rahim. Fetal gene therapy for neurodegenerative disease of infants. Nature Medicine. 2018; 24 (9):1317-1323.

Chicago/Turabian Style

Giulia Massaro; Citra N. Z. Mattar; Andrew M. S. Wong; Ernestas Sirka; Suzanne M. K. Buckley; Bronwen R. Herbert; Stefan Karlsson; Dany P. Perocheau; Derek Burke; Simon Heales; Angela Richard-Londt; Sebastian Brandner; Mylene Huebecker; David A. Priestman; Frances Platt; Kevin Mills; Arijit Biswas; Jonathan Cooper; Jerry K. Y. Chan; Seng H. Cheng; Simon N. Waddington; Ahad A. Rahim. 2018. "Fetal gene therapy for neurodegenerative disease of infants." Nature Medicine 24, no. 9: 1317-1323.

Journal article
Published: 15 July 2018 in Molecular Therapy - Nucleic Acids
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Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders.

ACS Style

John R. Counsell; Rajvinder Karda; Juan Antinao Diaz; Louise Carey; Tatiana Wiktorowicz; Suzanne M.K. Buckley; Shima Ameri; Joanne Ng; Julien Baruteau; Filipa Almeida; Rohan De Silva; Roberto Simone; Eleonora Lugarà; Gabriele Lignani; Dirk Lindemann; Axel Rethwilm; Ahad A. Rahim; Simon N. Waddington; Steven J. Howe. Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice. Molecular Therapy - Nucleic Acids 2018, 12, 626 -634.

AMA Style

John R. Counsell, Rajvinder Karda, Juan Antinao Diaz, Louise Carey, Tatiana Wiktorowicz, Suzanne M.K. Buckley, Shima Ameri, Joanne Ng, Julien Baruteau, Filipa Almeida, Rohan De Silva, Roberto Simone, Eleonora Lugarà, Gabriele Lignani, Dirk Lindemann, Axel Rethwilm, Ahad A. Rahim, Simon N. Waddington, Steven J. Howe. Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice. Molecular Therapy - Nucleic Acids. 2018; 12 ():626-634.

Chicago/Turabian Style

John R. Counsell; Rajvinder Karda; Juan Antinao Diaz; Louise Carey; Tatiana Wiktorowicz; Suzanne M.K. Buckley; Shima Ameri; Joanne Ng; Julien Baruteau; Filipa Almeida; Rohan De Silva; Roberto Simone; Eleonora Lugarà; Gabriele Lignani; Dirk Lindemann; Axel Rethwilm; Ahad A. Rahim; Simon N. Waddington; Steven J. Howe. 2018. "Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice." Molecular Therapy - Nucleic Acids 12, no. : 626-634.

Preprint
Published: 15 June 2018
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Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathways via a single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.

ACS Style

Julien Baruteau; Dany P. Perocheau; Joanna Hanley; Eridan Rocha Ferreira; Rajvinder Karda; Joanne Ng; Nattalie Suff; Ahad A. Rahim; Michael P. Hughes; Blerida Banushi; Helen Prunty; Mariya Hristova; Deborah A. Ridout; Alex Virasami; Simon Heales; Stewen J. Howe; Suzy M. Buckley; Philippa B. Mills; Paul Gissen; Simon N. Waddington; Jo Ng; Natalie Suff; Steven Howe; Suzanne Buckley. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. 2018, 348292 .

AMA Style

Julien Baruteau, Dany P. Perocheau, Joanna Hanley, Eridan Rocha Ferreira, Rajvinder Karda, Joanne Ng, Nattalie Suff, Ahad A. Rahim, Michael P. Hughes, Blerida Banushi, Helen Prunty, Mariya Hristova, Deborah A. Ridout, Alex Virasami, Simon Heales, Stewen J. Howe, Suzy M. Buckley, Philippa B. Mills, Paul Gissen, Simon N. Waddington, Jo Ng, Natalie Suff, Steven Howe, Suzanne Buckley. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. . 2018; ():348292.

Chicago/Turabian Style

Julien Baruteau; Dany P. Perocheau; Joanna Hanley; Eridan Rocha Ferreira; Rajvinder Karda; Joanne Ng; Nattalie Suff; Ahad A. Rahim; Michael P. Hughes; Blerida Banushi; Helen Prunty; Mariya Hristova; Deborah A. Ridout; Alex Virasami; Simon Heales; Stewen J. Howe; Suzy M. Buckley; Philippa B. Mills; Paul Gissen; Simon N. Waddington; Jo Ng; Natalie Suff; Steven Howe; Suzanne Buckley. 2018. "Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer." , no. : 348292.