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1. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia, Buddle, Sarah, Torres Montaguth, Oscar Enrique, Atkinson, Laura, Guerra-Assunção, José Afonso, Moradi Marjaneh, Mahdi, Zennezini Chiozzi, Riccardo, Storey, Nathaniel, Campos, Luis, Hutchinson, J. Ciaran, Counsell, John R., Pollara, Gabriele, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F., Siam, Ala’a, Tappouni, Luke J., Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S., Lennon, Alexander, McArdle, Andrew, Czap, Agata, Rosenheim, Joshua, Andrade, Catarina, Anderson, Glenn, Lee, Jack C. D., Williams, Rachel, Williams, Charlotte A., Tutill, Helena, Bayzid, Nadua, Martin Bernal, Luz Marina, Macpherson, Hannah, Montgomery, Kylie-Ann, Moore, Catherine, Templeton, Kate, Neill, Claire, Holden, Matt, Gunson, Rory, Shepherd, Samantha J., Shah, Priyen, Cooray, Samantha, Voice, Marie, Steele, Michael, Fink, Colin, Whittaker, Thomas E., Santilli, Giorgia, Gissen, Paul, Kaufer, Benedikt B., Reich, Jana, Andreani, Julien, Simmonds, Peter, Alrabiah, Dimah K., Castellano, Sergi, Chikowore, Primrose, Odam, Miranda, Rampling, Tommy, Houlihan, Catherine, Hoschler, Katja, Talts, Tiina, Celma, Cristina, Gonzalez, Suam, Gallagher, Eileen, Simmons, Ruth, Watson, Conall, Mandal, Sema, Zambon, Maria, Chand, Meera, Hatcher, James, De, Surjo, Baillie, Kenneth, Semple, Malcolm Gracie, Martin, Joanne, Ushiro-Lumb, Ines, Noursadeghi, Mahdad, Deheragoda, Maesha, Hadzic, Nedim, Grammatikopoulos, Tassos, Brown, Rachel, Kelgeri, Chayarani, Thalassinos, Konstantinos, Waddington, Simon N., Jacques, Thomas S., Thomson, Emma, Levin, Michael, Brown, Julianne R., and Breuer, Judith

Published
2023
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2. A dual AAV strategy for the treatment of Dravet Syndrome

Author

Antinao Diaz, Juan Francisco

Subjects
618.92
Abstract

Dravet Syndrome (DS) is an inherited childhood epilepsy caused by a mutation in the SCN1A gene, which encodes the voltage-gated sodium channel NaV 1.1. It has an incidence rate of 1:16,000 live births; patients suffer from refractory and generalized seizures that can evolve into status epilepticus, which can result in premature death. The disease is also associated with significant cognitive impairments. DS remains untreatable by either medical or surgical means. Gene therapy for DS is challenging; we and others (Feldman and Lossin, 2014) have experienced difficulties in propagating wild-type SCN1A plasmids in E.coli competent cells. Furthermore, the coding sequence of SCN1A (6kb) prevents its incorporation into an adeno-associated virus vector (AAV). This thesis describes an approach to overcome these problems by splitting SCN1A into two complementary halves. The hypothesis is that the dual AAV8-SCN1A constructs would produce polypeptides which would reconstitute post-transcriptionally into a functional NaV 1.1 protein (Stühmer et al., 1989). Two AAV8 vectors were designed; the two halves of SCN1A were driven by a pan neuronal promoter, human Synapsin. In vitro, co-transfection appeared toxic for cells, in a subset of recordings a small sodium current was observed. A knock-out mouse model was established and characterised to test these vectors in vivo. Unfortunately the treatment did not modify the phenotype of the knockout mice. I propose this was the result of insufficient number of cells expressing both vectors or that the split channel does not have the same characteristics as its full-length counterpart.

Published
2020

4. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, et al, Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, and et al

Abstract

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells. Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Published
2023

5. Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

Author

Ng, Joanne, primary, Barral, Serena, additional, De La Fuente Barrigon, Carmen, additional, Lignani, Gabriele, additional, Erdem, Fatma A., additional, Wallings, Rebecca, additional, Privolizzi, Riccardo, additional, Rossignoli, Giada, additional, Alrashidi, Haya, additional, Heasman, Sonja, additional, Meyer, Esther, additional, Ngoh, Adeline, additional, Pope, Simon, additional, Karda, Rajvinder, additional, Perocheau, Dany, additional, Baruteau, Julien, additional, Suff, Natalie, additional, Antinao Diaz, Juan, additional, Schorge, Stephanie, additional, Vowles, Jane, additional, Marshall, Lucy R., additional, Cowley, Sally A., additional, Sucic, Sonja, additional, Freissmuth, Michael, additional, Counsell, John R., additional, Wade-Martins, Richard, additional, Heales, Simon J. R., additional, Rahim, Ahad A., additional, Bencze, Maximilien, additional, Waddington, Simon N., additional, and Kurian, Manju A., additional

Published
2021
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6. Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth

Author

Suff, Natalie, primary, Karda, Rajvinder, additional, Antinao Diaz, Juan, additional, Ng, Joanne, additional, Baruteau, Julien, additional, Perocheau, Dany, additional, Taylor, Peter W., additional, Alber, Dagmar, additional, Buckley, Suzanne M.K., additional, Bajaj-Elliott, Mona, additional, Waddington, Simon N., additional, and Peebles, Donald, additional

Published
2019
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7. Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort

Author

Perocheau, Dany P., primary, Cunningham, Sharon C., additional, Lee, Juhee, additional, Antinao Diaz, Juan, additional, Waddington, Simon N., additional, Gilmour, Kimberly, additional, Eaglestone, Simon, additional, Lisowski, Leszek, additional, Thrasher, Adrian J., additional, Alexander, Ian E., additional, Gissen, Paul, additional, and Baruteau, Julien, additional

Published
2019
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8. Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors

Author

Karda, Rajvinder, primary, Rahim, Ahad A., additional, Wong, Andrew M.S., additional, Suff, Natalie, additional, Antinao Diaz, Juan, additional, Perocheau, Dany P., additional, Palomar Martin, Nuria, additional, Hughes, Michael, additional, Delhove, Juliette M.K.M., additional, Counsell, John R., additional, Cooper, Jonathan D., additional, Henckaerts, Els, additional, Mckay, Tristan R., additional, Buckley, Suzanne M.K., additional, and Waddington, Simon N., additional

Published
2018
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9. Creation of de novo cryptic splicing for ALS and FTD precision medicine.

Author

Wilkins, Oscar G., Chien, Max Z. Y. J., Wlaschin, Josette J., Barattucci, Simone, Harley, Peter, Mattedi, Francesca, Mehta, Puja R., Pisliakova, Maria, Ryadnov, Eugeni, Keuss, Matthew J., Thompson, David, Digby, Holly, Knez, Lea, Simkin, Rebecca L., Antinao Diaz, Juan, Zanovello, Matteo, Brown, Anna-Leigh, Darbey, Annalucia, Karda, Rajvinder, and Fisher, Elizabeth M. C.

Subjects
*AMYOTROPHIC lateral sclerosis, *RNA-binding proteins, *DEEP learning, *NEURODEGENERATION, *CHIMERIC proteins
Abstract

Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders. [ABSTRACT FROM AUTHOR]

Published
2024
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