INVESTIGADORES
PUNTEL Mariana
artículos
Título:
Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
Autor/es:
PUNTEL; MUHAMMAD; FARROKHI; VANDERVEEN; PARAN; APELHANS; KROEGER; SALEM; LACAYO; PECHNICK; KELSON; KENNEDY; PALMER; NG; LIU; KRASINKIEWICZ; LOWENSTEIN; CASTRO
Revista:
TOXICOLOGY AND APPLIED PHARMACOLOGY
Editorial:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Referencias:
Lugar: Amsterdam; Año: 2013 vol. 268 p. 318 - 330
ISSN:
0041-008X
Resumen:
Adenoviral vectors (Ads) are promising gene delivery vehicles due to
their high transduction efficiency; however, their clinical usefulness
has been hampered by their immunogenicity and the presence of anti-Ad
immunity in humans. We reported the efficacy of a gene therapy approach
for glioma consisting of intratumoral injection of Ads encoding
conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK)
and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3
(Ad-Flt3L). Herein, we report the biodistribution, efficacy, and
neurological and systemic effects of a bicistronic high-capacity Ad,
i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene
expression, even in the presence of anti-Ad immunity, and can encode
large therapeutic cassettes, including regulatory elements to enable
turning gene expression "on" or "off" according to clinical need. The
inclusion of two therapeutic transgenes within a single vector enables a
reduction of the total vector load without adversely impacting
efficacy. Because clinically the vectors will be delivered into the
surgical cavity, normal regions of the brain parenchyma are likely to be
transduced. Thus, we assessed any potential toxicities elicited by
escalating doses of HC-Ad-TK/TetOn-Flt3L (1×10(8), 1×10(9), or 1×10(10)
viral particles [vp]) delivered into the rat brain parenchyma. We
assessed neuropathology, biodistribution, transgene expression, systemic
toxicity, and behavioral impact at acute and chronic time points. The
results indicate that doses up to 1×10(9) vp of HC-Ad-TK/TetOn-Flt3L can
be safely delivered into the normal rat brain and underpin further
developments for its implementation in a phase I clinical trial for
glioma.