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1.
Mol Ther ; 32(7): 2052-2063, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38796703

RESUMEN

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for the treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5-capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-γ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.


Asunto(s)
Dependovirus , Factor VIII , Terapia Genética , Vectores Genéticos , Hemofilia A , Humanos , Hemofilia A/terapia , Hemofilia A/inmunología , Hemofilia A/genética , Dependovirus/genética , Dependovirus/inmunología , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Factor VIII/genética , Factor VIII/inmunología , Masculino , Adulto , Resultado del Tratamiento , Transgenes , Adulto Joven , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Persona de Mediana Edad
2.
J Thromb Haemost ; 22(5): 1263-1289, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38103734

RESUMEN

Adeno-associated virus gene therapy has been the subject of intensive investigation for monogenic disease gene addition therapy for more than 25 years, yet few therapies have been approved by regulatory agencies. Most have not progressed beyond phase 1/2 due to toxicity, lack of efficacy, or both. The liver is a natural target for adeno-associated virus since most serotypes have a high degree of tropism for hepatocytes due to cell surface receptors for the virus and the unique liver sinusoidal geometry facilitating high volumes of blood contact with hepatocyte cell surfaces. Recessive monogenic diseases such as hemophilia represent promising targets since the defective proteins are often synthesized in the liver and secreted into the circulation, making them easy to measure, and many do not require precise regulation. Yet, despite initiation of many disease-specific clinical trials, therapeutic windows are often nonexistent, resulting in excess toxicity and insufficient efficacy. Iterative progress built on these attempts is best illustrated by hemophilia, with the first regulatory approvals for factor IX and factor VIII gene therapies eventually achieved 25 years after the first gene therapy studies in humans. Although successful gene transfer may result in the production of sufficient transgenic protein to modify the disease, many emerging questions on durability, predictability, reliability, and variability of response have not been answered. The underlying biology accounting for these heterogeneous responses and the interplay between host and virus is the subject of intense investigation and the subject of this review.


Asunto(s)
Dependovirus , Terapia Genética , Vectores Genéticos , Hemofilia A , Hígado , Humanos , Dependovirus/genética , Hemofilia A/terapia , Hemofilia A/genética , Terapia Genética/métodos , Hígado/metabolismo , Hígado/virología , Animales , Factor VIII/genética , Factor VIII/metabolismo , Técnicas de Transferencia de Gen
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