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Current
Gene Therapy
ISSN: 1566-5232 - Volume 6, 6 Issues, 2006
Current Gene Therapy
Volume 6, Number 1, February 2006
Contents
Herpesvirus Saimiri-Based Gene Delivery Vectors Pp. 1-15
Rhoswyn A. Griffiths, James R. Boyne and Adrian Whitehouse
[Abstract]
Targeting Transcription Factors for Cancer Gene Therapy
Pp. 17-33
Towia A. Libermann and Luiz F. Zerbini
[Abstract]
Heparan Sulphate Proteoglycans and Viral Vectors : Ally or
Foe? Pp. 35-44
Romain R. Vivès, Hugues Lortat-Jacob and Pascal
Fender
[Abstract]
Gene Therapy Strategies Towards Immune Tolerance to Treat
the Autoimmune Diseases Pp. 45-58
Christopher Siatskas, James Chan, Judith Field, Kim
Murphy, Zeyad Nasa, Ban-Hock Toh and Frank Alderuccio
[Abstract]
Synthetic and Natural Polycations for Gene Therapy: State
of the Art and New Perspectives Pp. 59-71
Marcio J. Tiera, Françoise M. Winnik and Julio
C. Fernandes
[Abstract]
MDA-7/IL-24-Based Cancer Gene Therapy: Translation from the
Laboratory to the Clinic Pp. 73-91
Satoshi Inoue, Manish Shanker, Ryo Miyahara, Began
Gopalan, Suraag Patel, Yasuhisa Oida, Cynthia D. Branch, Anupama
Munshi, Raymond E. Meyn, Michael Andreeff, Fumihiro Tanaka,
Abner M. Mhashilkar, Sunil Chada and Rajagopal Ramesh
[Abstract]
Plasmid-Mediated Muscle-Targeted Gene Therapy for Circulating
Therapeutic Protein Replacement: A Tale of the Tortoise and
the Hare? Pp. 93-110
Jarupa Ratanamart and James A.M. Shaw
[Abstract]
Targeting DNA Repair Proteins: A Promising Avenue for Cancer
Gene Therapy Pp. 111-123
Jean-Philippe Belzile, Sibgat A. Choudhury, Denis
Cournoyer and Terry Y.-K. Chow
[Abstract]
The Neuroendocrine System as a Model to Evaluate Experimental
Gene Therapy Pp. 125-129
Claudia B. Hereñú, Oscar A. Brown, Yolanda
E. Sosa, Gustavo R. Morel, Paula C. Reggiani, Maria J. Bellini
and Rodolfo G. Goya
[Abstract]
RNA Based Gene Therapy for Dominantly Inherited Diseases Pp.
131-146
Richard Pelletier, Solenne O.P. Caron and Jack Puymirat
[Abstract]
Intracompartmental Delivery of CNTF as Therapy for Huntingtons
Disease and Retinitis Pigmentosa Pp. 147-159
Dwaine F. Emerich and Christopher G. Thanos
[Abstract]
Abstracts
[Back to top]
Herpesvirus Saimiri-Based Gene Delivery Vectors
Rhoswyn A. Griffiths, James R. Boyne and Adrian Whitehouse
Herpesviruses possess a number of characteristics which make
them promising gene delivery vectors. These include their
capacity to package large amounts of heterologous DNA and
an ability to establish persistent, lifelong infections, where
the viral genome remains as a circular non-integrated episome.
Herpesvirus saimiri (HVS) is the prototype gamma-2 herpesvirus
and is currently being developed as a potential gene delivery
vector. In addition to the above properties, HVS-based vectors
have the ability to infect a wide range of human cell lines
and primary cultures with high efficiencies. Moreover, upon
infection the viral genome persists as high copy number, circular,
non-integrated episomes which segregate to progeny cells upon
division. This allows the HVS-based vector to stably transduce
a dividing cell population and provide sustained heterologous
gene expression. As such, it offers the characteristics of
an artificial chromosome combined with a highly efficient
delivery system. This review aims to describe the assessment
of HVS-based vectors in both in vitro and in
vivo studies, highlighting new developments and possible
applications for the treatment of genetic diseases.
[Back to top]
Targeting Transcription Factors for Cancer Gene Therapy
Towia A. Libermann and Luiz F. Zerbini
A high proportion of oncogenes and tumor suppressor genes
encode transcription factors. Deregulated expression or activation
and inactivation of transcription factors as well as mutations
and translocations play critical roles in tumorigenesis. Furthermore,
the majority of oncogenic signaling pathways converge on sets
of transcription factors that ultimately control gene expression
patterns resulting in tumor formation and progression as well
as metastasis. Under normal physiological conditions whole
sets of genes with similar functions are regulated by highly
specific, tightly regu-lated upstream transcriptional regulators,
whereas in cancer aberrant activation of these transcription
factors leads to de-regulated expression of multiple gene
sets associated with tumor development and progression. The
activity of these transcription factors can be modulated by
multiple mechanisms including posttranslational modifications.
Activation or inactivation of transcription factors promote
cancer development, cell survival and proliferation and induce
tumor angio-genesis. Since many of these transcription factors
are inactive under normal physiological conditions and their
expres-sion and activities are tightly regulated, these transcription
factors represent highly desirable and logical points of thera-peutical
interference in cancer development and progression. Three
major families of transcription factors have emerged as important
players in human cancer and are validated targets in drug
discovery for cancer therapy: 1) the NF-κB
and AP-1 families of transcription factors, 2) the STAT family
members and 3) the steroids receptors. This review aims to
elucidate the divergent molecular mechanisms involved in the
deregulated activation of transcription factor signaling in
malignant transformation, although additional transcription
factor families such as the Ets factors, ATF family members,
basic helix-loop-helix transcription factors etc. are additional
critical transcriptional regulators in human cancer. We ex-plore
new approaches to specifically inhibit these transcription
factors in cancer in order to validate them as a drug tar-gets.
Efforts to develop novel viral vectors for therapeutic applications
are also discussed.
[Back to top]
Heparan Sulphate Proteoglycans and Viral Vectors : Ally
or Foe?
Romain R. Vivès, Hugues Lortat-Jacob and Pascal
Fender
The attachment of viruses to the host cell surface is a
critical stage that will largely condition cell permissivity
and productive infection. The understanding of such mechanisms
is therefore essential for gene therapy applications involving
viruses, as this step will influence both targeting and delivery
efficiency of the gene of interest. Viral attach-ment depends
upon the recognition and binding of viral envelope/capsid
proteins to specific cellular receptors that can be from very
diverse origins. Amongst them are heparan sulphate proteoglycans
(HSPGs), a family of glycoproteins which, through the large
binding properties of their heparan sulphate (HS) polysaccharide
chains, serve as attachment receptor for a great number of
viruses. The aim of this review is to provide an update on
the multiple roles of HSPGs during viral infection, with a
special focus on viruses used as gene delivery vectors. Consequences
of HS binding for gene therapy applications will be assessed,
as well as the various strategies that have been developed
to potentiate the advantages or to overcome the drawbacks
resulting from viral vector interaction with HS.
[Back to top]
Gene Therapy Strategies Towards Immune Tolerance to Treat
the Autoimmune Diseases
Christopher Siatskas, James Chan, Judith Field, Kim
Murphy, Zeyad Nasa, Ban-Hock Toh and Frank Alderuccio
Autoimmune diseases such as type 1 diabetes and multiple
sclerosis pose a significant health burden on our society.
As a whole, autoimmune diseases affect approximately 6% of
the population and are the third largest disease burden after
heart disease and cancer. Such pathologic manifestations arise
by way of damaging reactions of B-cell derived antibodies
and/or T-cells to self-antigens and are triggered by genetic
and environmental factors. Currently there is no known cure,
with treatment restricted to toxic, long-term immunosuppressive
regimes, replacement therapy and in in-tractable cases, transplantation
of autologous or allogeneic haematopoietic stem cells. In
experimental models of auto-immunity, gene therapeutic approaches
have demonstrated promise in treating the autoimmune diseases.
These include delivery of anti-inflammatory cytokines and
exploitation of regulatory T cells. However, none of these
approaches pro-vide lasting, long-term benefit. We hypothesise
that therapeutically transduced haematopoietic stem cells
followed by transplantation is an alternative strategy to
establish permanent immune tolerance that can not only prevent
autoimmu-nity but also cure these diseases. Our approach is
focused on directing autoimmune disease-specific autoantigen
expres-sion in the thymus by genetic manipulation of haematopoietic
stem cells to establish molecular chimeras. Our hypothesis
originates from experimental studies with a mouse model of
experimental autoimmune gastritis (EAG) and more re-cently
with the non-obese diabetic (NOD) mouse model for type 1 diabetes
(T1D).
[Back to top]
Synthetic and Natural Polycations for Gene Therapy: State
of the Art and New Perspectives
Marcio J. Tiera, Françoise M. Winnik and Julio
C. Fernandes
Currently, the major drawback of gene therapy is the gene
transfection rate. The two main types of vectors that are
used in gene therapy are based on viral or non-viral gene
delivery systems. There are several non-viral systems that
can be used to transfer foreign genetic material into the
human body. In order to do so, the DNA to be transferred must
escape the processes that affect the disposition of macromolecules.
These processes include the interaction with blood components,
vascular endothelial cells and uptake by the reticuloendothelial
system. Furthermore, the degradation of therapeutic DNA by
serum nucleases is also a potential obstacle for functional
delivery to the target cell. Cationic po-lymers have a great
potential for DNA complexation and may be useful as non-viral
vectors for gene therapy applica-tions. The objective of this
review was to address the state of the art in gene therapy
using synthetic and natural polyca-tions and the latest strategies
to improve the efficiency of gene transfer into the cell.
[Back to top]
MDA-7/IL-24-Based Cancer Gene Therapy: Translation from
the Laboratory to the Clinic
Satoshi Inoue, Manish Shanker, Ryo Miyahara, Began
Gopalan, Suraag Patel, Yasuhisa Oida, Cynthia D. Branch, Anupama
Munshi, Raymond E. Meyn, Michael Andreeff, Fumihiro Tanaka,
Abner M. Mhashilkar, Sunil Chada and Rajagopal Ramesh
Despite recent advances in treatment strategies, the overall
5-year survival rate for patients with common epithelial cancers
is poor largely because of the difficulty in treating metastatic
cancers. Therefore, therapeutic agents are urgently needed
that can effectively inhibit both primary epithelial tumors
and their metastases. One such agent that has shown promise
in preclinical studies is the tumor suppressor/cytokine, melanoma
differentiation associated gene-7 also known as interleukin-24
(mda-7/IL-24).
Preclinical studies from our and other laboratories have
shown that overexpression of MDA-7/IL-24 causes a strong tu-mor-
suppressive effect in many human cancer cells but spares normal
cells. This gene therapy also enhances the tumor-suppressive
activity of radiotherapy and chemotherapy. Secreted MDA-7
protein that is glycosylated also has been shown to have potent
antiangiogenic activity both in vitro and in
vivo. Studies examining the immune properties of mda-7
have shown that MDA-7/IL-24 unlike the related IL-10, functions
as a Th1 cytokine. Recently, an MDA-7 protein-mediated “bystander
effect” on tumor cells has been documented. Building
on these findings we successfully completed a Phase I clinical
trial of adenovirus-based mda-7 cancer therapy that confirmed
the safety of this gene therapy. Phase II trials evaluating
the efficacy of mda-7-based gene therapy are warranted. The
outcome of such ongoing mda-7-based gene therapy trials will
allow us to better understand this therapy’s clinical
utility.
[Back to top]
Plasmid-Mediated Muscle-Targeted Gene Therapy for Circulating
Therapeutic Protein Replacement: A Tale of the Tortoise and
the Hare?
Jarupa Ratanamart and James A.M. Shaw
There is now conclusive evidence that gene therapy can lead
to real clinical benefit. Initial enthusiasm has been muted
by set-backs related to viral vectors including retroviral
oncogenesis and adenoviral inflammatory response. Plasmid-mediated
muscle-targeted gene transfer offers the potential of a cost-effective
pharmaceutical grade therapy delivered by simple intramuscular
injection without the need for anaesthetic, cell culture,
transplantation or immunosuppression. This approach is particularly
appropriate for long-term circulating therapeutic protein
replacement currently requiring repeated injection therapy.
Wide-ranging clinical applications include haemophilia, chronic
anaemia, growth hormone deficiency and diabetes. Inadequate
transgene expression, unregulated protein delivery and immune
response have been major limiting factors. Recent innovations
including in situ electroporation enabling sustained
systemic protein delivery within the therapeutic range are
reviewed. Pharmacological and physiological approaches to
regulation are discussed in addition to the role of innate
and humoral immunity. Translation of advances in all of these
areas to clinical success will enable muscle-targeted gene
therapy to capitalise on its inherent strengths and realise
its long-standing promise.
[Back to top]
Targeting DNA Repair Proteins: A Promising Avenue for Cancer
Gene Therapy
Jean-Philippe Belzile, Sibgat A. Choudhury, Denis
Cournoyer and Terry Y.-K. Chow
Enhanced DNA repair in many cancer cells can be correlated
to the resistance to cancer treatment, and thus contributes
to a poor prognosis. Ionizing radiation and many anti-cancer
drugs induce DNA double-strand breaks (DSBs), which are usually
regarded as the most toxic types of DNA damages. Repair of
DNA DSBs is vital for maintaining genomic stability and hence
crucial for survival and propagation of all cellular organisms.
Therefore, reducing the capacity of cancer cells to repair
DSBs could sensitize tumors to radio/chemotherapy. Many investigators
have used gene therapy strategies to down-regulate or inactivate
proteins involved in the repair of DSBs in order to reduce
the survival of cancer cells. Herein, are reviewed several
protein candidates that have been targeted by different gene
therapy approaches. Results obtained from in vitro
and in vivo experiments are presented and discussed
in the perspective of potential gene therapy clinical trials.
[Back to top]
The Neuroendocrine System as a Model to Evaluate Experimental
Gene Therapy
Claudia B. Hereñú, Oscar A. Brown, Yolanda
E. Sosa, Gustavo R. Morel, Paula C. Reggiani, Maria J. Bellini
and Rodolfo G. Goya
The implementation of experimental gene therapy in animal
models of neurological diseases is an area of growing interest.
Although the neuroendocrine system offers unique advantages
for the assessment of in vivo gene therapy, little
work has been done in this model. Here we review the core
of documented studies in which in vivo gene therapy
has been implemented in the neuroendocrine system of rodent
models. In the hypothalamus, restorative gene therapy has
been successfully implemented in Brattleboro rats, an arginine
vasopressin (AVP) mutant which suffers from diabetes insipidus,
in Koletsky (fak/fak) and in Zucker
(fa/fa) rats which have leptin receptor mutations
that render them obese, hyperphagic and hyperinsulinemic.
In the above models, viral vectors expressing AVP, leptin
receptor b and proopiomelanocortin, respectively were stereotaxically
injected in the relevant hypothalamic regions. In rats, aging
brings about a progressive degeneration and loss of hypothalamic
tuberoinfundibular dopaminergic neurons, which are involved
in the tonic inhibitory control of prolactin secretion and
lactotrophic cell proliferation. Stereotaxic injection of
an adenoviral vector expressing Insulin-like Growth Factor-I
(IGF-I) was able to correct their chronic hyperprolactinemia
and restore tuberoinfundibular dopaminergic (TIDA) neuron
numbers. In young and old F-344 male rats, Glial Cell Line-derived
Neurotrophic Factor (GDNF) gene delivery in the hypothalamus
induced body weight loss. These results suggest that further
implementation of gene therapy strategies in neuroendocrine
models may be highly rewarding.
[Back to top]
RNA Based Gene Therapy for Dominantly Inherited Diseases
Richard Pelletier, Solenne O.P. Caron and Jack Puymirat
There are numerous examples in the literature of gene therapy
applications for recessive disorders. There are precious few
instances, however, of studies conducted to treat dominantly
inherited pathologies. The reasons are simple: there are fewer
cases of dominantly inherited diseases on one hand, but mostly
it is far easier to correct recessive mutations than dominant
ones. Typically recessive mutations cause a loss of (or reduced)
gene function which can be compensated for by introduction
of a replacement allele into the cell. In contrast, dominant
negative mutations not only display impaired function, but
also exhibit a novel one that is pathologic to the cell. Treating
these conditions by gene therapy implies silencing the dominant
allele without altering the expression of the wild-type gene.
We describe here different strategies aimed at silencing dominant
mutations through mRNA destruction and provide examples of
their application to known autosomal dominant diseases. An
overview of the most common molecular tools (antisense DNA
and RNA, ribozymes and RNA interference) suitable to utilize
these strategies is also presented and we discuss the relevant
aspects involved in the choice of a particular approach in
a gene therapy experiment.
[Back to top]
Intracompartmental Delivery of CNTF as Therapy for Huntingtons
Disease and Retinitis Pigmentosa
Dwaine F. Emerich and Christopher G. Thanos
Ciliary neurotrophic factor (CNTF) is a cytokine with neurotrophic
activity across a broad spectrum of peripheral and central
nervous system (CNS) cells. While its therapeutic potential
for CNS diseases has been clear for sometime, the blood brain
barrier (BBB) hinders the systemic delivery of CNTF and direct
bolus injections are not suitable due to the short half-life
of CNTF. One means of overcoming the BBB while providing continuous
delivery of CNTF is with immunoisolated cellular implants
that produce and deliver CNTF directly to the region of interest.
Cells can be protected from host rejection by encapsulating,
or surrounding, them within an immunoisolatory, semipermeable
membrane that admits oxygen and required nutrients and releases
bioactive cell secretions, but restricts passage of larger
cytotoxic agents from the host immune defense system. The
selective membrane eliminates the need for chronic im-munosuppression
of the host and allows the implanted cells to be obtained
from nonhuman sources. In this review we discuss cell immunoisolation
for Huntington’s disease and retinitis pigmentosa. These
two indications are highlighted because of extensive pre-clinical
data supporting the general concept and recent clinical data
that both strengthens the theoretical role of CNTF for treating
neurodegeneration and justifies additional clinical evaluation
in these and other diseases.
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