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Current
Gene Therapy
ISSN: 1566-5232
Current Gene Therapy
Volume 8, Number 2, April 2008
Contents
Viral Vectors in Cancer Immunotherapy: Which Vector
for Which Strategy? Pp. 66-78
Sara A. Collins, Barbara-ann Guinn, Patrick T. Harrison, Martina
F. Scallan, Gerald C. O’Sullivan and Mark Tangney
[Abstract]
Virus-based Gene Transfer Approaches and Adipose
Tissue Biology Pp. 79-87
Louis Casteilla, Béatrice Cousin, Valérie
Planat-Benard, Patrick Laharrague, Mamen Carmona and Luc Pénicaud
[Abstract]
Virotherapy as An Approach Against Cancer Stem
Cells Pp. 88-96
Camilla Ribacka and Akseli Hemminki
[Abstract]
The Poxvirus Vectors MVA and NYVAC as Gene Delivery
Systems for Vaccination Against Infectious Diseases and Cancer
Pp. 97-120
Carmen E. Gómez, José L. Nájera,
Magdalena Krupa and Mariano Esteban
[Abstract]
Gene Transfer to Sperm and Testis: Future Prospects
of Gene Therapy for Male Infertility Pp. 121-134
Yoshiyuki Kojima, Satoshi Kurokawa, Kentaro Mizuno, Yukihiro
Umemoto, Shoichi Sasaki, Yutaro Hayashi and Kenjiro Kohri
[Abstract]
Human Hematopoietic Stem Cells in Gene Therapy:
Pre-Clinical and Clinical Issues Pp. 135-146
Alessandra Biffi and Martina Cesani
[Abstract]
Abstracts
[Back to top]
Viral Vectors in Cancer Immunotherapy: Which
Vector for Which Strategy?
Sara A. Collins, Barbara-ann Guinn, Patrick T. Harrison, Martina
F. Scallan, Gerald C. O’Sullivan and Mark Tangney
Gene therapy involves the transfer of genetic information
to a target cell to facilitate the production of therapeutic
proteins and is now a realistic prospect as a cancer treatment.
Gene transfer may be achieved through the use of both viral
and non-viral delivery methods and the role of this method
in the gene therapy of cancer has been demonstrated. Viruses
represent an attractive vehicle for cancer gene therapy due
to their high efficiency of gene delivery. Many viruses can
mediate long term gene expression, while some are also capable
of infecting both dividing and non-dividing cells. Given the
broadly differing capabilities of various viral vectors, it
is imperative that the functionality of the virus meets the
requirements of the specific treatment. A number of immunogene
therapy strategies have been undertaken, utilising a range
of viral vectors, and studies carried out in animal models
and patients have demonstrated the therapeutic potential of
viral vectors to carry genes to cancer cells and induce anti-tumour
immune responses. This review critically discusses the advances
in the viral vector mediated delivery of immunostimulatory
molecules directly to tumour cells, the use of viral vectors
to modify tumour cells, the creation of whole cell vaccines
and the direct delivery of tumour antigens in animal models
and clinical trials, specifically in the context of the suitability
of vector types for specific strategies.
[Back to top]
Virus-based Gene Transfer Approaches and Adipose Tissue Biology
Louis Casteilla, Béatrice Cousin, Valérie
Planat-Benard, Patrick Laharrague, Mamen Carmona and Luc Pénicaud
The status of adipose tissue changes rapidly. From a
simple filler tissue, it successively acquires the status
of metabolic active tissue, endocrine tissue, plastic tissue,
and finally that of a large reservoir of cells suitable for
cell therapy and regenerative medicine. All throughout this
story, our knowledge has been largely dependent on genetic
tools and gene transfer. Now, the time has come where gene
transfer in adipose derived cells can be envisioned, not only
for understanding the role or importance of one gene, but
also to engineer adipose derived cells for the purpose of
therapy by delivering secreted products. In this paper, after
a brief overview of adipose tissues, a large part will be
devoted to the use of virus-based gene transfer in transducing
adipose tissue and cells which reside therein. We also critically
review the use of adipose “specific” promoters
and the applications already described in the literature.
[Back to top]
Virotherapy as An Approach Against Cancer Stem Cells
Camilla Ribacka and Akseli Hemminki
It has been hypothesized that cancers originate from a small
population of cells with stem cell-like characteristics, including
self-renewal and pluripotency. Such tumor-initiating cells,
also referred to as cancer stem cells, are thought to account
for relapses following seemingly successful treatments, because
their slow turnover and capacity for expelling anti-tumor
drugs leaves them untouched by conventional treatment regimens.
Targeting of cancer stem cells might be key for improving
survival and producing cures in patients with metastatic tumors.
Viruses enter cells though infection and might therefore not
be sensitive to stem cell resistance mechanisms. During the
last decades, oncolytic adenoviruses have been shown to effectively
kill cancer cells, by seizing control of their DNA replication
machinery and utilizing it for the production of new virions,
ultimately resulting in the rupture of the cell. Human safety
data in cancer trials has been excellent even when the dose
of administered adenovirus has been high. Future approaches
include additional modifications of the adenoviral genome
that prime them to attack cancer stem cells specifically,
utilizing linage-specific cell surface markers, dysfunctional
stem cell signaling pathways or up-regulated oncogenic genes.
However, already existing oncolytic adenoviruses have displayed
potential to efficiently kill not only differentiated cancer
cells, but also tumor-initiating stem cells. Here, we review
the current literature that supports the existence of cancer
stem cells and discuss the potential of virotherapy for killing
tumor-initiating cells.
[Back to top]
The Poxvirus Vectors MVA and NYVAC as Gene Delivery Systems
for Vaccination Against Infectious Diseases and Cancer
Carmen E. Gómez, José L. Nájera,
Magdalena Krupa and Mariano Esteban
Recombinants based on poxviruses have been used extensively
as gene delivery systems to study many biological functions
of foreign genes and as vaccines against many pathogens, particularly
in the veterinary field. Based on safety record, efficient
expression and ability to trigger specific immune responses,
two of the most promising poxvirus vectors for human use are
the attenuated modified vaccinia virus Ankara (MVA) and the
Copenhagen derived NYVAC strains. Because of the scientific
and clinical interest in these two vectors, here we review
their biological characteristics, with emphasis on virus-host
cell interactions, viral immunomodulators, gene expression
profiling, virus distribution in animals, and application
as vaccines against different pathogens and tumors.
[Back to top]
Gene Transfer to Sperm and Testis: Future Prospects of Gene
Therapy for Male Infertility
Yoshiyuki Kojima, Satoshi Kurokawa, Kentaro Mizuno, Yukihiro
Umemoto, Shoichi Sasaki, Yutaro Hayashi and Kenjiro Kohri
Male infertility has been considered a major contributory
factor to infertility. The causes of spermatogenetic failure
found in most cases of male infertility remain largely idiopathic.
Unfortunately, there is no effective treatment to improve
spermatogenesis for idiopathic male infertility patients.
Intracytoplasmic sperm injection (ICSI) is the current treatment
of choice for severe male infertility and has brought the
joy of childbearing to couples for whom it was previously
impossible; however, several problems exist with this treatment.
In addition, if there are no spermatozoa in the testis of
these patients, they do not have paternity potential even
if ICSI is conducted. Ultimately, fertilization is better
in vivo than in vitro. Recently, on the
other hand, gene transfer to sperm and testis has been developed
to find more effective and simple methods to obtain transgenic
animals. This technique has the potential to be the most useful
approach for the future treatment of male infertility. In
this review, we will give an overview of the recent advanced
technique of gene transfer to sperm and testis, and discuss
the future prospects of gene therapy for the treatment of
male infertility. In conclusion, although more investigations
on the mechanism of spermatogenesis and male infertility and
the establishment of techniques for more efficient and safer
gene transfer to the sperm and testis will be needed, gene
therapy will enable a revolutionary advance for reproductive
treatment and provide great benefit for patients with male
infertility in the future.
[Back to top]
Human Hematopoietic Stem Cells in Gene Therapy: Pre-Clinical
and Clinical Issues
Alessandra Biffi and Martina Cesani
Hematopoietic stem and progenitor cells (HSC) have been
widely used in allogeneic transplant procedures, therefore
their intrinsic characteristics, the biology of their niche
in the bone marrow, and the mobilization and homing processes
have been extensively investigated. With the development of
gene therapy strategies, new therapeutic options based on
autologous HSC have become available which may reduce the
morbidity and mortality associated to allogeneic transplantation,
but require an ex vivo manipulation of the cells
to be corrected before re-infusion. For the success of these
approaches it is necessary to optimize culture conditions
in order to achieve efficient cell transduction while preserving
the biological properties of the stem cells. We review here
the factors critical for achieving efficient HSC transduction
and maintenance of HSC stemness and homing capacity upon ex
vivo culture.
When HSC gene therapy is used in genetic disorders, permanent
integration of therapeutic genes into the chromosomes of affected
cells is needed. Indeed, by use of integrating vectors, such
as retroviruses, gene therapy has met significant success
in immunodeficiency syndromes characterized by a selective
advantage of the transduced cells. However, retroviral integration
can take place in stem cells at a variety of chromosomal sites,
and examples have been reported of integration of therapeutic
vectors causing cancer in patients. The clinical benefit arising
from the long-term correction of the genetic defect, due to
vector integration into the HSC genome, and the adverse consequences
of these events are also here discussed, together with the
new and challenging perspectives of HSC gene therapy.
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