Development of oncolytic and gene therapy vectors based on adenovirus serotype 4 as an alternative to adenovirus serotype 5.
J Gene Med
; 26(1): e3576, 2024 Jan.
Article
en En
| MEDLINE
| ID: mdl-37580111
ABSTRACT
BACKGROUND:
Adenoviral vectors are among the most frequently used vectors for gene therapy and cancer treatment. Most vectors are derived from human adenovirus (Ad) serotype 5 despite limited applicability caused by pre-existing immunity and unfavorable liver tropism, whereas the other more than 100 known human serotypes remain largely unused. Here, we screened a library of human Ad types and identified Ad4 as a promising candidate vector.METHODS:
Reporter-gene-expressing viruses representative of the natural human Ad diversity were used to transduce an array of muscle cell lines and two- or three-dimensional tumor cultures. The time-course of transgene expression was monitored by fluorescence or luminescence measurements. To generate replication-deficient Ad4 vector genomes, successive homologous recombination was applied.RESULTS:
Ad4, 17 and 50 transduced human cardiomyocytes more efficiently than Ad5, whereas Ad37 was found to be superior in rhabdomyocytes. Despite its moderate transduction efficiency, Ad4 showed efficient and long-lasting gene expression in papillomavirus (HPV) positive tumor organoids. Therefore, we aimed to harness the potential of Ad4 for improved muscle transduction or oncolytic virotherapy of HPV-positive tumors. We deleted the E1 and E3 transcription units to produce first generation Ad vectors for gene therapy. The E1- and E1/E3-deleted vectors were replication-competent in HEK293 cells stably expressing E1 but not in the other cell lines tested. Furthermore, we show that the Ad5 E1 transcription unit can complement the replication of E1-deleted Ad4 vectors.CONCLUSIONS:
Our Ad4-based gene therapy vector platform contributes to the development of improved Ad vectors based on non-canonical serotypes for a broad range of applications.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Adenovirus Humanos
/
Infecciones por Papillomavirus
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
J Gene Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania