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Current
Gene Therapy
ISSN: 1566-5232
Current Gene Therapy
Volume 8, Number 3, June 2008
Contents
Episomal Vectors for Gene Therapy Pp.
147-161
Anja Ehrhardt, Rudolf Haase, Aloys Schepers, Manuel J. Deutsch,
Hans J. Lipps and Armin Baiker
[Abstract]
Measles Virus as An Oncolytic Vector Platform
Pp. 162-175
Boris Blechacz and Stephen J. Russell
[Abstract]
Erythropoietic Porphyrias: Animal Models and
Update in Gene-Based Therapies Pp. 176-186
Emmanuel Richard, Elodie Robert-Richard, Cécile
Ged, François Moreau-Gaudry and Hubert de Verneuil
[Abstract]
Gene Therapy for Gastric Diseases Pp.
187-200
Shintaro Fumoto, Junya Nishi, Junzo Nakamura and Koyo
Nishida
[Abstract]
Cystic Fibrosis, Vector-Mediated Gene Therapy,
and Relevance of Toll-Like Receptors: A Review of Problems,
Progress, and Possibilities Pp. 201-207
Timothy J. Atkinson
[Abstract]
Non-Engineered, Naturally Oncolytic Herpes Simplex
Virus HSV1 HF-10: Applications for Cancer Gene Therapy
Pp. 208-221
Akihiro Nawa, ChenHong Luo, Lumin Zhang, Yoko Ushjima,
Daisuke Ishida, Maki Kamakura, Yasushi Fujimoto, Fumi Goshima,
Fumitaka Kikkawa and Yukihiro Nishiyama
[Abstract]
Abstracts
[Back to top]
Episomal Vectors for Gene Therapy
Anja Ehrhardt, Rudolf Haase, Aloys Schepers, Manuel J. Deutsch,
Hans J. Lipps and Armin Baiker
The increasing knowledge of the molecular and genetic
background of many different human diseases has led to the
vision that genetic engineering might be used one day for
their phenotypic correction. The main goal of gene therapy
is to treat loss-of-function genetic disorders by delivering
correcting therapeutic DNA sequences into the nucleus of a
cell, allowing its long-term expression at physiologically
relevant levels. Manifold different vector systems for the
therapeutic gene delivery have been described over the recent
years. They all have their individual advantages but also
their individual limitations and must be judged on a careful
risk/benefit analysis. Integrating vector systems can deliver
genetic material to a target cell with high efficiency enabling
long-term expression of an encoded transgene. The main disadvan-tage
of integrating vector systems, however, is their potential
risk of causing insertional mutagenesis. Episomal vector systems
have the potential to avoid these undesired side effects,
since they behave as separate extrachromosomal elements in
the nucleus of a target cell. Within this article we present
a comprehensive survey of currently available episomal vector
systems for the genetic modification of mammalian cells. We
will discuss their advantages and disadvantages and their
applications in the context of basic research, biotechnology
and gene therapy.
[Back to top]
Measles Virus as An Oncolytic Vector Platform
Boris Blechacz and Stephen J. Russell
Viral vector systems are widely being used in the development
of new genetic approaches for a variety of human diseases.
Oncolytic viruses have shown great potential as cancer therapeutics.
The ideal viral vector for cancer gene therapy eradicates
a clinically significant fraction of malignant cells and leaves
normal tissues unharmed. The Edmonston vaccine strain of measles
virus is a replicating RNA virus which is characterized by
its tumor selectivity and oncolysis. Its strong tumor suppressive
potential combined with its excellent safety record as a viral
vaccine makes it an optimal platform for oncolytic virotherapy
of cancer. Recent advances in genetic engineering of measles
virus allow insertion of therapeutic and diagnostic transgenes
as well as complete retargeting of measles virus. These strategies
resulted in the generation of recombinant measles viruses
allowing non-invasive monitoring of viral replication and
viral spread. The immune defense is a significant barrier
for efficient viral gene therapy. Immune-evasive strategies
have successfully been developed for measles virus enhancing
its efficacy. This review gives an overview of measles virus
as an anticancer agent; in particular, its use in oncologic
virotherapy as well as new developments in targeting and immune
evasive strategies.
[Back to top]
Erythropoietic Porphyrias: Animal Models and Update in Gene-Based
Therapies
Emmanuel Richard, Elodie Robert-Richard, Cécile
Ged, François Moreau-Gaudry and Hubert de Verneuil
The inherited porphyrias are inborn errors of haem biosynthesis,
each resulting from the deficient activity of a specific enzyme
of the haem biosynthetic pathway. Porphyrias are divided into
erythropoietic and hepatic according to the predominant porphyrin-accumulating
tissue. Three different erythropoietic porphyrias (EP) have
been described: erythro-poietic protoporphyria (EPP, MIM 177000)
the most frequent, congenital erythropoietic porphyria (CEP,
MIM 263700), and the very rare hepatoerythropoietic porphyria
(HEP, MIM 176100). Bone marrow transplantation is considered
as the only curative treatment for severe cases of erythropoietic
porphyria (especially CEP), if donors are available. Some
EPP patients who undergo liver failure may require hepatic
transplantation. Murine models of EPP and CEP have been developed
and mimic most of the human disease features. These models
allow a better understanding of the pathophysiological mechanisms
involved in EP as well as the development of new therapeutic
strategies. The restoration of deficient enzymatic activity
in the bone marrow compartment following gene therapy has
been extensively studied. Murine oncoretroviral, and recently,
lentiviral vectors have been successfully used to transduce
hematopoietic stem cells, allowing full metabolic and phenotypic
correction of both EPP and CEP mice. In CEP, a selective survival
advantage of corrected cells was demonstrated in mice, reinforcing
the arguments for a gene therapy approach in the human disease.
These successful results form the basis for gene therapy clinical
trials in severe forms of erythropoietic porphyrias.
[Back to top]
Gene Therapy for Gastric Diseases
Shintaro Fumoto, Junya Nishi, Junzo Nakamura and Koyo
Nishida
Gene therapy for gastric cancer and gastric ulcer is
a rationalized strategy since various genes correlate with
these diseases. Since gene expressions in non-target tissues/cells
cause side effects, a selective gene delivery system targeted
to the stomach and/or cancer must be developed. The route
of vector transfer (direct injection, systemic, intraperitoneal,
gastric serosal surface and oral administration) is an important
issue which can determine efficacy and safety. Strategies
for cancer gene therapy can be categorized as suicide gene
therapy, growth inhibition and apoptosis induction, immu-notherapy,
anti-angiogenesis, and others. Combination of the target gene
with other genes and/or strategies such as chemo-therapy and
virotherapy is promising. Candidates for treatment of gastric
ulcer are vascular endothelial growth factor, an-giopoietin-1,
serum response factor, and cationic host defense peptide cathelicidin.
In this review, we discuss stomach- and cancer-targeted gene
transfer methods and summarize gene therapy trials for gastric
cancer and gastric ulcer.
[Back to top]
Cystic Fibrosis, Vector-Mediated Gene Therapy, and Relevance
of Toll-Like Receptors: A Review of Problems, Progress, and
Possibilities
Timothy J. Atkinson
Gene delivery in cystic fibrosis is hampered by extracellular
and intracellular biological barriers and inefficient vectors.
Although progress is evident, continued bioengineering of
DNA, vectors, and delivery technologies will be critical to
ensure biocompatibility, safety, and therapeutic effectiveness.
Both viral and nonviral vectors demonstrate insufficient gene
expression to adequately correct chloride ion and respiratory
homeostasis, but vector modifications and novel vector types
continue to advance understanding of transfection processes,
immunobiological responses, and cystic fibrosis pathology.
Interactions of toll-like receptors and other coreceptors
may be critical components of cystic fibrosis immuno-biology
but additional research will be needed before causative associations
are widely established; however, receptor modulation provides
a theoretical framework to develop new therapeutic approaches.
Clinical-phase pharmacotherapies offer short-term promise
to restore electrolyte imbalance and/or symptomatology, but
it may be many years before gene therapy offers a curative
solution for the disease.
[Back to top]
Non-Engineered, Naturally Oncolytic Herpes Simplex Virus HSV1
HF-10: Applications for Cancer Gene Therapy
Akihiro Nawa, ChenHong Luo, Lumin Zhang, Yoko Ushjima,
Daisuke Ishida, Maki Kamakura, Yasushi Fujimoto, Fumi Goshima,
Fumitaka Kikkawa and Yukihiro Nishiyama
Oncolytic HSV-1 has been developed as a novel anticancer
agent. According to the properties and functions of HSV-1
encoded proteins, several genes have been targeted for engineering
of oncolytic HSV-1. As a result, a variety of strategies have
been applied to the engineering of oncolytic HSV-1. Success
in cancer therapy for solid tumors requires a maximal oncolytic
effect; however, recombinant HSV-1 that has been adapted to
meet neurotoxicity requirements for the treatment of brain
tumors may be too highly attenuated for effective use in solid
tumors outside the brain. Recently, there has been renewed
interest in the high potency of naturally oncolytic viruses.
In this review, we will overview the engineered oncolytic
HSV developed thus far, as well as its mechanism of selectivity
and its mode of spreading within tumors. We also discuss the
preclinical and clinical studies of HF-10, a non-engineered
oncolytic HSV-1 virus, and its potential for use in cancer
gene therapy.
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