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Article: Evaluation of diversity indices to estimate clonal dominance in gene therapy studies.

Corre, Guillaume / Galy, Anne

Molecular therapy. Methods & clinical development

2023 Volume 29, Page(s) 418–425

Abstract: In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been ... ...

Abstract	In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been associated with possible risks of insertional mutagenesis leading to clonal dominance, monitoring the relative abundance of individual vector insertion sites in patients' blood cells has become an important safety assessment, particularly in hematopoietic stem cell-based therapies. Clinical studies often express clonal diversity using various metrics. One of the most commonly used is the Shannon index of entropy. However, this index aggregates two distinct aspects of diversity, the number of unique species and their relative abundance. This property hampers the comparison of samples with different richness. This prompted us to reanalyze published datasets and to model the properties of various indices as applied to the evaluation of clonal diversity in gene therapy. A normalized version of the Shannon index, such as Pielou's index, or Simpson's probability index is robust and useful to compare sample evenness between patients and trials. Clinically meaningful standard values for clonal diversity are herein proposed to facilitate the use of vector insertion site analyses in genomic medicine practice.
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.05.003
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Article ; Online: Deciphering the Molecular Mechanism of Incurable Muscle Disease by a Novel Method for the Interpretation of miRNA Dysregulation.

Israeli, David / Vu Hong, Ai / Corre, Guillaume / Miagoux, Quentin / Richard, Isabelle

Non-coding RNA

2022 Volume 8, Issue 4

Abstract: It is now well-established that microRNA dysregulation is a hallmark of human diseases, and that aberrant expression of miRNA is not randomly associated with human pathologies but plays a causal role in the pathological process. Investigations of the ... ...

Abstract	It is now well-established that microRNA dysregulation is a hallmark of human diseases, and that aberrant expression of miRNA is not randomly associated with human pathologies but plays a causal role in the pathological process. Investigations of the molecular mechanism that links miRNA dysregulation to pathophysiology can therefore further the understanding of human diseases. The biological effect of miRNA is thought to be mediated principally by miRNA target genes. Consequently, the target genes of dysregulated miRNA serve as a proxy for the biological interpretation of miRNA dysregulation, which is performed by target gene pathway enrichment analysis. However, this method unfortunately often fails to provide testable hypotheses concerning disease mechanisms. In this paper, we describe a method for the interpretation of miRNA dysregulation, which is based on miRNA host genes rather than target genes. Using this approach, we have recently identified the perturbations of lipid metabolism, and cholesterol in particular, in Duchenne muscular dystrophy (DMD). The host gene-based interpretation of miRNA dysregulation therefore represents an attractive alternative method for the biological interpretation of miRNA dysregulation.
Language	English
Publishing date	2022-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna8040048
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Article ; Online: Lentiviral standards to determine the sensitivity of assays that quantify lentiviral vector copy numbers and genomic insertion sites in cells.

Corre, Guillaume / Seye, Ababacar / Frin, Sophie / Ferrand, Maxime / Winkler, Kathrin / Luc, Cyril / Dorange, Fabien / Rocca, Céline J / Galy, Anne

Gene therapy

2022 Volume 29, Issue 9, Page(s) 536–543

Abstract: With an increasing number of gene therapy clinical trials and drugs reaching the market, it becomes important to standardize the methods that evaluate the efficacy and safety of gene therapy. We herein report the generation of lentiviral standards which ... ...

Abstract	With an increasing number of gene therapy clinical trials and drugs reaching the market, it becomes important to standardize the methods that evaluate the efficacy and safety of gene therapy. We herein report the generation of lentiviral standards which are stable, cloned human cells prepared from the diploid HCT116 cell line and which carry a known number of lentiviral vector copies in their genome. These clones can be used as reference cellular materials for the calibration or qualification of analytical methods that quantify vector copy numbers in cells (VCN) or lentiviral vector genomic integration sites (IS). Cellular standards were used to show the superior precision of digital droplet PCR (ddPCR) over quantitative PCR (qPCR) for VCN determination. This enabled us to develop a new sensitive and specific VCN ddPCR method specific for the integrated provirus and not recognizing the transfer plasmid. The cellular standards, were also useful to assess the sensitivity and limits of a ligation-mediated PCR (LM-PCR) method to measure IS showing that at least 1% abundance of a single IS can be detected in a polyclonal population but that not all IS can be amplified with similar efficiency. Thus, lentiviral standards should be systematically used in all assays that assess lentiviral gene therapy efficacy and safety.
MeSH term(s)	DNA Copy Number Variations ; Genetic Therapy ; Genomics ; Humans ; Real-Time Polymerase Chain Reaction
Language	English
Publishing date	2022-02-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/s41434-022-00315-8
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Zs.A 3991: Show issues

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Article ; Online: Author Correction: miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy.

Sanson, Mathilde / Vu Hong, Ai / Massourides, Emmanuelle / Bourg, Nathalie / Suel, Laurence / Amor, Fatima / Corre, Guillaume / Bénit, Paule / Barthelemy, Inès / Blot, Stephane / Bigot, Anne / Pinset, Christian / Rustin, Pierre / Servais, Laurent / Voit, Thomas / Richard, Isabelle / Israeli, David

Scientific reports

2024 Volume 14, Issue 1, Page(s) 7441

Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-57483-3
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Article ; Online: An empowered, clinically viable hematopoietic stem cell gene therapy for the treatment of multisystemic mucopolysaccharidosis type II.

Das, Sabyasachi / Rruga, Fatlum / Montepeloso, Annita / Dimartino, Agnese / Spadini, Silvia / Corre, Guillaume / Patel, Janki / Cavalca, Eleonora / Ferro, Francesca / Gatti, Alessandra / Milazzo, Rita / Galy, Anne / Politi, Letterio S / Rizzardi, Gian Paolo / Vallanti, Giuliana / Poletti, Valentina / Biffi, Alessandra

Molecular therapy : the journal of the American Society of Gene Therapy

2024 Volume 32, Issue 3, Page(s) 619–636

Abstract: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem ... ...

Abstract	Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new hematopoietic stem cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof of concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon-optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard vs. a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof of concept for the clinical translation of this approach for the treatment of Hunter syndrome.
MeSH term(s)	Humans ; Animals ; Mice ; Mucopolysaccharidosis II/therapy ; Mucopolysaccharidosis II/drug therapy ; Iduronate Sulfatase/genetics ; Iduronate Sulfatase/metabolism ; Genetic Therapy ; Central Nervous System/metabolism ; Lentivirus/genetics ; Lentivirus/metabolism ; Hematopoietic Stem Cells/metabolism
Chemical Substances	Iduronate Sulfatase (EC 3.1.6.13)
Language	English
Publishing date	2024-02-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2024.01.034
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Zs.A 5640: Show issues

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Article ; Online: Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells.

Parmentier, Romuald / Racine, Laëtitia / Moussy, Alice / Chantalat, Sophie / Sudharshan, Ravi / Papili Gao, Nan / Stockholm, Daniel / Corre, Guillaume / Fourel, Geneviève / Deleuze, Jean-François / Gunawan, Rudiyanto / Paldi, Andras

PLoS biology

2022 Volume 20, Issue 10, Page(s) e3001849

Abstract: When human cord blood-derived CD34+ cells are induced to differentiate, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. In particular, the cells pass through a transitory phase known as " ... ...

Abstract	When human cord blood-derived CD34+ cells are induced to differentiate, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. In particular, the cells pass through a transitory phase known as "multilineage-primed" state. These cells are characterized by a mixed gene expression profile, different in each cell, with the coexpression of many genes characteristic for concurrent cell lineages. The aim of our study is to understand the mechanisms of the establishment and the exit from this transitory state. We investigated this issue using single-cell RNA sequencing and ATAC-seq. Two phases were detected. The first phase is a rapid and global chromatin decompaction that makes most of the gene promoters in the genome accessible for transcription. It results 24 h later in enhanced and pervasive transcription of the genome leading to the concomitant increase in the cell-to-cell variability of transcriptional profiles. The second phase is the exit from the multilineage-primed phase marked by a slow chromatin closure and a subsequent overall down-regulation of gene transcription. This process is selective and results in the emergence of coherent expression profiles corresponding to distinct cell subpopulations. The typical time scale of these events spans 48 to 72 h. These observations suggest that the nonspecificity of genome decompaction is the condition for the generation of a highly variable multilineage expression profile. The nonspecific phase is followed by specific regulatory actions that stabilize and maintain the activity of key genes, while the rest of the genome becomes repressed again by the chromatin recompaction. Thus, the initiation of differentiation is reminiscent of a constrained optimization process that associates the spontaneous generation of gene expression diversity to subsequent regulatory actions that maintain the activity of some genes, while the rest of the genome sinks back to the repressive closed chromatin state.
MeSH term(s)	Humans ; Chromatin/genetics ; Cell Lineage/genetics ; Genome ; Cell Differentiation/genetics ; Gene Expression
Chemical Substances	Chromatin
Language	English
Publishing date	2022-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3001849
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Article: An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress.

Israeli, David / Cosette, Jérémie / Corre, Guillaume / Amor, Fatima / Poupiot, Jérôme / Stockholm, Daniel / Montus, Marie / Gjata, Bernard / Richard, Isabelle

Molecular therapy. Methods & clinical development

2019 Volume 13, Page(s) 494–502

Abstract: Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which ... ...

Abstract	Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress.
Language	English
Publishing date	2019-05-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2019.04.007
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Article ; Online: Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy.

Amor, Fatima / Vu Hong, Ai / Corre, Guillaume / Sanson, Mathilde / Suel, Laurence / Blaie, Stephanie / Servais, Laurent / Voit, Thomas / Richard, Isabelle / Israeli, David

Journal of cachexia, sarcopenia and muscle

2021 Volume 12, Issue 3, Page(s) 677–693

Abstract: Background: Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in ... ...

Abstract	Background: Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca Methods: We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4-8, 8-12, and 12-20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results: We identified 96 dysregulated miRNAs (adjusted P-value <0.1), of which 74 were up-regulated and 22 were down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs, and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP-1 and SREBP-2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters. Conclusions: This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.
MeSH term(s)	Animals ; Cholesterol/metabolism ; Humans ; Lipid Metabolism ; Male ; Mice ; Mice, Inbred mdx ; Muscle, Skeletal/metabolism ; Muscular Dystrophy, Duchenne/genetics
Chemical Substances	Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2021-05-26
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2586864-0
ISSN	2190-6009 ; 2190-5991
ISSN (online)	2190-6009
ISSN	2190-5991
DOI	10.1002/jcsm.12708
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Article ; Online: Efficacité et sécurité du traitement par thérapie génique des patients atteints du syndrome de Wiskott-Aldrich.

Galy, Anne / Corre, Guillaume / Cavazzana, Marina / Hacein-Bey-Abina, Salima

Medecine sciences : M/S

2015 Volume 31, Issue 12, Page(s) 1066–1069

Title translation	Efficacy and safety of gene therapy for Wiskott-Aldrich syndrome.
MeSH term(s)	Adolescent ; Child ; Child, Preschool ; Genetic Therapy/adverse effects ; Humans ; Infant ; Treatment Outcome ; Wiskott-Aldrich Syndrome/genetics ; Wiskott-Aldrich Syndrome/therapy
Language	French
Publishing date	2015-12
Publishing country	France
Document type	News
ZDB-ID	632733-3
ISSN	1958-5381 ; 0767-0974
ISSN (online)	1958-5381
ISSN	0767-0974
DOI	10.1051/medsci/20153112006
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Article ; Online: Constraints on Human CD34+ Cell Fate due to Lentiviral Vectors Can Be Relieved by Valproic Acid.

Moussy, Alice / Papili Gao, Nan / Corre, Guillaume / Poletti, Valentina / Majdoul, Saliha / Fenard, David / Gunawan, Rudiyanto / Stockholm, Daniel / Páldi, András

Human gene therapy

2019 Volume 30, Issue 8, Page(s) 1023–1034

Abstract: The initial stages following ... ...

Abstract	The initial stages following the
MeSH term(s)	Biomarkers ; Cell Differentiation/drug effects ; Fetal Blood/cytology ; Gene Expression ; Gene Transfer Techniques ; Genetic Vectors/genetics ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Lentivirus/genetics ; Phenotype ; Transduction, Genetic ; Transgenes ; Valproic Acid/pharmacology ; Virus Integration
Chemical Substances	Biomarkers ; Valproic Acid (614OI1Z5WI)
Language	English
Publishing date	2019-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2019.009
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