Polyfunctional T cells and unique cytokine clusters imprint the anti rAAV2/rAAV9 vector immune response DOI Creative Commons
Stephan Holtkamp,

Florian R. Lagoda,

Adam Lister

et al.

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

Published: Nov. 25, 2024

Polyfunctional T cells programmed to perform activities such as degranulation of lytic enzymes and simultaneous production multiple cytokines are associated with more effective control viral infections. Immune responses recombinant adeno-associated virus (rAAV) vector delivery systems can critically influence therapeutic efficacy safety gene therapy. However, knowledge polyfunctional in anti-AAV immune is scarce. To bridge this gap, we have investigated the polyfunctionality primary human CD4 from healthy donors after

Language: Английский

Understanding AAV vector immunogenicity: from particle to patient DOI Creative Commons
Bijay Dhungel,

Ian Winburn,

Candida da Fonseca Pereira

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(3), P. 1260 - 1288

Published: Jan. 1, 2024

Gene therapy holds promise for patients with inherited monogenic disorders, cancer, and rare genetic diseases.Naturally occurring adeno-associated virus (AAV) offers a well-suited vehicle clinical gene transfer due to its lack of significant pathogenicity amenability be engineered deliver therapeutic transgenes in variety cell types long-term sustained expression.AAV has been bioengineered produce recombinant AAV (rAAV) vectors many therapies that are approved or late-stage development.However, ongoing challenges hamper wider use rAAV vector-mediated therapies.These include immunity against vectors, limited transgene packaging capacity, sub-optimal tissue transduction, potential risks insertional mutagenesis vector shedding.This review focuses on aspects rAAV, mediated by anti-AAV neutralizing antibodies (NAbs) arising after natural exposure AAVs administration.We provide an in-depth analysis factors determining seroprevalence examine approaches managing NAbs pre-and post-vector administration.Methodologies used quantify NAb levels strategies overcome pre-existing also discussed.The broad adoption will require appreciation their current limitations further research mitigate impact.

Language: Английский

Citations

16
Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A DOI

Alok Srivastava,

Aby Abraham,

Fouzia N. Aboobacker

et al.

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Severe hemophilia A is managed with factor VIII replacement or hemostatic products that stop prevent bleeding. Data on gene therapy hematopoietic stem-cell (HSC)-based expression of for the treatment severe are lacking.

Language: Английский

Citations

8
Revolutionizing therapeutics: Unleashing the power of extracellular vesicles for disease intervention DOI Creative Commons
S. Ghosal,

Bernadett R. Bodnár,

Brachyahu Meir Kestecher

et al.

Current Opinion in Physiology, Journal Year: 2025, Volume and Issue: unknown, P. 100815 - 100815

Published: Jan. 1, 2025

Language: Английский

Citations

0
Pre-existing Anti-AAV9 Antibodies in the Chinese Healthy and Rare Disease Populations: Implications for Gene Therapy DOI Creative Commons

Qian Zhao,

Shuangqing Yu,

Diyi Fu

et al.

Virus Research, Journal Year: 2025, Volume and Issue: unknown, P. 199549 - 199549

Published: Feb. 1, 2025

Language: Английский

Citations

0
Hurdles to healing: Overcoming cellular barriers for viral and nonviral gene therapy DOI Creative Commons

Steffen Honrath,

Michael Burger, Jean‐Christophe Leroux

et al.

International Journal of Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown, P. 125470 - 125470

Published: March 1, 2025

Language: Английский

Citations

0
CoreTIA: a modular, statistically robust transduction inhibition assay for AAV neutralization DOI

Beatrix Kovács,

Fanni Somogyi,

Viktória Szabó

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

Abstract Adeno-associated virus (AAV) gene therapy is often limited by pre-existing neutralizing antibodies (NAbs), yet current assays for NAb detection lack standardization and rarely quantify uncertainty, complicating cross-study comparisons. We present coreTIA (core Transduction Inhibition Assay), a modular experimental protocol combined with statistically robust analysis pipeline that delivers precise, reproducible titers quantified uncertainty every result. coreTIA’s statistical framework enables estimation of neutralization even when dilution series are incomplete, helping to reduce repeat testing minimizing sample volume requirements. Evaluation refinement key assay parameters support consistent performance across AAV serotypes. By providing suite as an open resource, facilitates more transparent measurement, potentially aiding harmonization regulatory assessment, addressing barrier progress in research development.

Language: Английский

Citations

0
Unveiling the sex bias: higher preexisting and neutralizing titers against AAV in females and implications for gene therapy DOI

Stephanee Warrington,

Trish T. Hoang,

Morten Seirup

et al.

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

Published: May 5, 2025

Language: Английский

Citations

0
A single dose recombinant AAV based CHIKV vaccine elicits robust and durable protective antibody responses in mice DOI Creative Commons

Qin-Xuan Zhu,

Yanan Zhang, Hongqing Zhang

et al.

PLoS neglected tropical diseases, Journal Year: 2024, Volume and Issue: 18(11), P. e0012604 - e0012604

Published: Nov. 4, 2024

Background Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that responsible for fever, which characterized by rash, and debilitating polyarthralgia. Since its re-emergence in 2004, CHIKV has continued to spread new regions become severe health threat global public. Development of safe single dose vaccines provide durable protection desirable control the virus. The recombinant adeno-associated (rAAV) vectors represent promising vaccine platform prolonged with single-dose immunization. In this study, we developed rAAV capsid serotype 1 vector based evaluated effect against challenge. Methodology AAV1 encoding full-length structural proteins (named as rAAV1-CHIKV-SP) was generated vitro transfecting plasmids AAV helper-free system into HEK-293T cells. safety immunogenicity rAAV1-CHIKV-SP were tested 4-week-old C57BL/6 mice. antibody responses mice receiving prime-boost or immunization determined ELISA plaque reduction neutralizing test. immunized challenged evaluate vaccine. Conclusions showed remarkable A intramuscular injection elicited high level long-lasting responses, conferred complete heterologous strain These results suggest represents candidate different clades simplified strategy.

Language: Английский

Citations

2
Seroprevalence of binding and neutralizing antibodies against 18 adeno-associated virus types in patients with neuromuscular disorders DOI Creative Commons
Xiaoyan Wang,

Patrick Julian Klann,

Ellen Wiedtke

et al.

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

Published: Sept. 27, 2024

High levels of pre-existing antibodies are a major challenge for the application viral vectors since they can severely limit their efficacy. To identify promising candidates among adeno-associated virus (AAV) based future gene therapies treatment hereditary neuromuscular disorders (NMDs), we investigated antibody in sera from patients with NMDs against 18 AAV types, including 11 AAVs wild-type capsids, 5 peptide-modified capsids and 2 shuffled capsids. With regard to capsid AAVs, lowest binding were detected AAV6, AAV5, AAV12 AAV9, whereas highest AAV10, AAV8, AAV1, AAV2. The neutralizing AAV12, AAV7, AAV8 AAV13, AAV2 AAV3. Interestingly, influence peptide modifications or shuffling on neutralization seemed depend parental AAV. While sex serum donors had no significant impact levels, observed trend higher older some types clear positive correlation titers age donors. disease status other hand did not have meaningful changes neutralization. Our data indicate that several may be good therapeutic due low potential recipients rather than health has biggest vector applicability.

Language: Английский

Citations

1
Gene Therapy for Inherited Liver Disease: To Add or to Edit DOI Open Access
Yue Chen, Niek P. van Til, Piter J. Bosma

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12514 - 12514

Published: Nov. 21, 2024

Patients suffering from an inherited severe liver disorder require lifelong treatment to prevent premature death. Until recently, the only curative option was transplantation, which requires immune suppression. Now, liver-directed gene therapy, is a much less invasive procedure, has become market-approved for hemophilia A and B. This may pave way it of choice many other recessive disorders with loss-of-function mutations. Inherited disease toxic-gain-of-function or intrinsic hepatocyte damage alternative applications, such as integrating vectors genome editing technologies, that can provide permanent specific modification genome. We present overview currently available therapy strategies, i.e., supplementation, editing, repair investigated in preclinical clinical studies treat disorders. The advantages limitations these applications are discussed relation underlying mechanism.

Language: Английский

Citations

1