Gene Therapy in the Light of Lifestyle Diseases: Budesonide, Acetaminophen and Simvastatin Modulates rAAV Transduction Efficiency DOI Creative Commons
Żaneta Słyk,

Natalia Stachowiak,

Maciej Małecki

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(9), P. 1213 - 1213

Published: Sept. 14, 2024

Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection dividing and nondividing cells, the presence tissue-specific serotypes, biosafety considerations. This study investigates impact commonly used therapeutic drugs—acetaminophen, budesonide, simvastatin—on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an mosaic vector under control a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction was assessed by qPCR microscopy. Analysis functional interactions between genes potentially involved drug-exposed cells also performed. showed clear effect drugs on transmission. Notably, acetaminophen enhanced 9-fold, while budesonide simvastatin 2-fold 3-fold increases, respectively. The analysis illustrates possible involvement related cell membranes potentiation induced investigation. Attention should be paid S100A8, which is common drug-modified showing anti-inflammatory effects (budesonide simvastatin), demonstrating interaction receptor (HGFR). underscores significance assessing pharmacokinetics/pharmacodynamics (PKs/PDs) drug–gene optimizing protocols.

Language: Английский

Liver‐directed gene therapy for inherited metabolic diseases DOI Creative Commons
Julien Baruteau, Nicola Brunetti‐Pierri, Paul Gissen

et al.

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 47(1), P. 9 - 21

Published: Jan. 1, 2024

Abstract Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene products have now been approved based monogenic disorders. Liver‐directed has recently become an option treatment of haemophilias and is likely to one the favoured therapeutic strategies in near future. In this review, we present different vectors liver‐targeting, including editing. We highlight current development viral nonviral a number urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson glycogen storage disease Type Ia, phenylketonuria maple syrup urine disease. describe main limitations open questions further development: immunogenicity, inflammatory response, genotoxicity, administration fibrotic liver. The follow‐up constantly growing treated patients allows better understanding its benefits provides design safer more efficacious treatments. Undoubtedly, liver‐targeting offers promising avenue innovative therapies with unprecedented potential address unmet needs suffering from diseases.

Language: Английский

Citations

14
Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy DOI
Pasqualina Colella

Molecular Diagnosis & Therapy, Journal Year: 2024, Volume and Issue: 28(6), P. 703 - 719

Published: Aug. 12, 2024

Language: Английский

Citations

3
DNA Contamination Within Recombinant Adeno Associated Virus (AAV) Preparations Correlates with Decreased CD34+ Cell Clonogenic Potential DOI Creative Commons
Christopher R. Luthers,

Sung-Min Ha,

Annika Mittelhauser

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(4), P. 101334 - 101334

Published: Sept. 12, 2024

Language: Английский

Citations

3
Filtering through AAV Capsid Libraries for Effective Kidney Gene Transfer DOI
Aravind Asokan, Matthew H. Wilson

Kidney International, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Thrombotic Microangiopathy Associated with Systemic Adeno-Associated Virus Gene Transfer: Review of Reported Cases DOI
Genevieve Laforet

Human Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon clinical setting been limited by incomplete data and a lack uniform diagnostic reporting criteria. While apparently rare available information, AAV-associated TMA/aHUS can pose substantial risk to patients including one published fatality. Reported cases were originally pediatric Duchenne muscular dystrophy receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently reported both adult across range disorders, transgenes, promoters, AAV capsid types. This article provides introduction complement system, TMA aHUS, anticomplement therapies, then presents reviews publicly. Finally, exploration factors current future mitigation approaches are discussed.

Language: Английский

Citations

0
Challenges in Humoral Immune Response to Adeno-Associated Viruses Determination DOI Open Access
Daria A. Naumova,

Tatyana Krokunova,

Denis Maksimov

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 816 - 816

Published: Jan. 19, 2025

Adeno-associated viruses (AAVs) are non-pathogenic, replication-deficient that have gained widespread attention for their application as gene therapy vectors. While these vectors offer high transduction efficiency and long-term expression, the host immune response poses a significant challenge to clinical success. This review focuses on obstacles evaluating humoral AAVs. We discuss problems with validation of in vitro tests possible approaches overcome them. Using published data neutralizing titers AAV serotypes, we built first antigenic maps AAVs order visualize relationships between varying serotypes.

Language: Английский

Citations

0
AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain DOI Creative Commons
Helena Costa Verdera, Vasco Meneghini,

Zachary Fitzpatrick

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 18, 2025

Adeno-associated viral (AAV) vector-based gene therapy is gaining foothold as treatment for genetic neurological diseases with encouraging clinical results. Nonetheless, dose-dependent adverse events have emerged in recent trials through mechanisms that remain unclear. We modelled here the impact of AAV transduction cell models human central nervous system (CNS), taking advantage induced pluripotent stem cells. Our work uncovers vector-induced innate immune contribute to death. While empty capsids were well tolerated, genome triggered p53-dependent DNA damage responses across CNS types followed by induction inflammatory responses. In addition, transgene expression led MAVS-dependent activation type I interferon Formation foci neurons and gliosis confirmed murine striatum upon intraparenchymal injection. Transduction-induced death could be prevented inhibiting p53 or acting downstream on STING- IL-1R-mediated Together, our identifies vector sensing can potentially AAV-associated neurotoxicity.

Language: Английский

Citations

0
Characterization of residual microRNAs in AAV vector batches produced in HEK293 mammalian cells and Sf9 insect cells DOI Creative Commons
Magalie Penaud‐Budloo,

Émilie Lecomte,

Quentin Lecomte

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(3), P. 101305 - 101305

Published: July 26, 2024

Language: Английский

Citations

2
Essential role of pre-existing humoral immunity in TLR9-mediated type I IFN response to recombinant AAV vectors in human whole blood DOI Creative Commons
Nada S. Alakhras, Christopher A. Moreland,

Li Chin Wong

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 28, 2024

Recombinant adeno-associated virus (AAV) vectors have emerged as the preferred platform for gene therapy of rare human diseases. Despite clinical promise, host immune responses to AAV and transgene remain a major barrier development successful AAV-based therapies. Here, we assessed innate response AAV9, serotype AAV-mediated CNS. We showed that AAV9 induced type I interferon (IFN) IL-6 in blood from healthy donors. This was replicated with AAV6, required full viral particles, but not observed every donor. Depleting CpG motifs or inhibiting TLR9 signaling reduced IFN responding donors, highlighting importance TLR9-mediated DNA sensing AAV9. Remarkably, further demonstrated only seropositive donors preexisting antibodies capsid mounted an whole anti-AAV9 were necessary sufficient promote release plasmacytoid dendritic (pDC) cell activation Thus, our study reveals previously unidentified requirement blood.

Language: Английский

Citations

1
AAV vectors trigger DNA damage responses and STING-dependent inflammation in human CNS cells DOI Creative Commons
Helena Costa Verdera, Vasco Meneghini,

Zachary Fitzpatrick

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: April 10, 2024

Abstract Adeno-associated viral (AAV) vector-based gene therapy is gaining foothold as a treatment option for variety of genetic neurological diseases with encouraging clinical results. Nonetheless, dose-dependent toxicities and severe adverse events have emerged in recent trials through mechanisms that remain unclear. We modelled here the impact AAV transduction context cell models human central nervous system (CNS), taking advantage induced pluripotent stem cell-based technologies. Our work uncovers vector-induced cell-intrinsic innate immune contribute to apoptosis 2D 3D models. While empty capsids were well tolerated, genome triggered p53-dependent DNA damage responses across CNS types followed by induction IL-1R- STING-dependent inflammatory responses. In addition, transgene expression led MAVS-dependent signaling activation type I interferon (IFN) Cell-intrinsic paracrine onset could be prevented inhibiting p53 or acting downstream STING- IL-1R-mediated Activation damage, IFN inflammation confirmed vivo , mouse model. Together, our identifies cell-autonomous vector sensing can potentially AAV-associated neurotoxicity.

Language: Английский

Citations

1