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Current Gene Therapy
ISSN: 1566-5232
Current Gene Therapy
Volume 5, Number 5, October 2005
Contents
HSV-1-Derived Recombinant and Amplicon Vectors for Gene Transfer
and Gene Therapy Pp.445
Alberto L. Epstein, Peggy Marconi, Rafaela Argnani
and
Roberto Manservigi
[Abstract]
The Use of Gene Therapy Tools in Reproductive Immunology Research
Pp.459
Ana C. Zenclussen, Maria L. Zenclussen, Thomas Ritter
and Hans D. Volk
[Abstract]
RNA Splicing Manipulation: Strategies to Modify Gene Expression
for a Variety of Therapeutic Outcomes Pp.467
Steve D. Wilton and Susan Fletcher
[Abstract]
Recent Advances in the Development of Adenovirus- and Poxvirus-Vectored
Tuberculosis Vaccines Pp.485
Zhou Xing, Michael Santosuosso, Sarah McCormick, Teng-Chih
Yang, James Millar, Mary Hitt, Yonghong Wan, Jonathan Bramson
and H. M. Vordermeier
[Abstract]
Animal Models for Growth Hormone Gene Therapy Pp.493
Cibele N. Peroni, Peter W. Gout and Paolo Bartolini
[Abstract]
Genetic Idiotypic and Tumor Cell-Based Vaccine Strategies
for Indolent Non Hodgkin’s Lymphoma Pp.511
Pier A. Ruffini, Massimo Di Nicola, Carmelo Carlo-Stella,
Salvatore Siena and Alessandro M. Gianni
[Abstract]
Immune Response to Herpes Simplex Virus and γ134.5
Deleted HSV Vectors Pp.523
Eeva K. Broberg and Veijo Hukkanen
[Abstract]
Erratum Pp.531
[Abstract]
Abstracts
[Back to top]
HSV-1-Derived Recombinant and Amplicon Vectors for Gene
Transfer and Gene Therapy
Alberto L. Epstein,Peggy Marconi,Rafaela Argnani and
Roberto Manservigi
Herpes simplex virus type 1 (HSV-1) is a major human pathogen
whose lifestyle is based on a long-term dual interaction with
the infected host characterized by the existence of lytic
and latent infections. Although in most cell types infection
with HSV-1 will induce toxic effects ending in the death of
the infected cells, the very deep knowledge we possess on
the genetics and molecular biology of HSV-1 has permitted
the deletion of most toxic genes and the de-velopment of non-pathogenic
HSV-1-based vectors for gene transfer. Several unique features
of HSV-1 make vectors de-rived from this virus very appealing
for preventive or therapeutic gene transfer. These include
(i) the very high trans-genic capacity of the virus particle,
authorizing to convey very large pieces of foreign DNA to
the nucleus of mammalian cells, (ii) the genetic complexity
of the virus genome, allowing to generate many different types
of attenuated vectors possessing oncolytic activity, and (iii)
the ability of HSV-1 vectors to invade and establish lifelong
non-toxic latent in-fections in neurons from sensory ganglia
and probably in other neurons as well, from where transgenes
can be strongly and long-term expressed. Three different classes
of vectors can be derived from HSV-1: replication-competent
attenuated vectors, replication-incompetent recombinant vectors,
and defective helper-dependent vectors known as amplicons.
Each of these different vectors attempts to exploit one or
more of the above-mentioned features of HSV-1. In this review
we will update the current know-how concerning design, construction,
and recent applications, as well as the potential and current
limitations of the three different classes of HSV-1-based
vectors.
[Back to top]
The Use of Gene Therapy Tools in Reproductive Immunology
Research
Ana C. Zenclussen,Maria L. Zenclussen,Thomas Ritter
and Hans D. Volk
Mammalian pregnancy is a complex phenomenon allowing the
maternal immune system to support its allogeneic fetus, while
still being effective against pathogens. Gene therapy approaches
have the potential to treat devastating inherited diseases
for which there is a little hope of finding a conventional
cure. In reproductive medicine, experimental trials have been
made so far only for correcting gene defects in utero.
The use of gene therapy for improving pregnancyrate success
or avoiding pregnancy-related diseases i.e. miscarriage or
pre-eclampsia, remains a very distant goal with unresolved
moral and ethical aspects. However, gene therapy may help
determining the role of several genes in supporting fetal
growth and/or avoiding its rejection experimentally and might
further help to identify new targets of intervention. Gene
therapy strategies to avoid fetal rejection may include the
transfer and expression of cytoprotective molecules locally
at the fetal-placental interface. In addition, the ex-vivo
genetic modification of immune cells for tolerance induction
is a novel and tempting approach. In this regard, we have
confirmed the role of the cyto-protective and immunomodulatory
molecule Heme Oxygenase-1 (HO-1), by treating animals undergoing
abortion with an adenovirus coding for HO-1. Since the sole
application of a control vector did not provoke deleterious
effects in pregnancy outcome, we propose the use of experimental
gene therapy for unveiling molecular and cellular pathways
leading to pregnancy success.
[Back to top]
RNA Splicing Manipulation: Strategies to Modify Gene Expression
for a Variety of Therapeutic Outcomes
Steve D. Wilton and Susan Fletcher
Antisense oligonucleotides initially offered great hope as
specific compounds to modify gene expression, primarily through
RNaseH induced degradation of the target transcript. Expansion
of the field led to new chemistries capable of invoking different
mechanisms, including suppression of protein synthesis by
translational blockade, and there is now a major interest
in downregulation of gene expression using short interfering
RNAs to induce RNA silencing. Naturally occurring microRNAs
have been implicated in the regulation of gene expression.
This review considers examples of antisense oligonucleotides
redirecting the process of exon recognition and intron removal
during gene transcript splicing. While suppression of gene
expression is necessary to address some conditions, it appears
likely that there may be many more clinical applications for
antisense oligonucleotides in redirecting splicing patterns.
Pre-mRNA splicing is a tightly co-ordinated, multifactorial
process, which can be disrupted by antisense oligonucleotides
in a highly specific manner, allowing either suppression of
aberrant splicing, by-pass of nonsense or frame-shifting mutations
or alteration of spliceoform ratios. Manipulation of splicing
patterns has been applied to a diverse range of conditions,
including β-thalassemia, Duchenne muscular dystrophy,
spinal muscular atrophy and certain cancers. Alternative exon
usage has been identified as a major mechanism for generating
diversity from a limited repertoire of genes in higher eukaryotes.
Considering that up to 75% of all human primary gene transcripts
are reported to be alternatively spliced, intervention at
the level of pre-mRNA processing is likely to become increasingly
significant in the fight against genetic and acquired disorders.
[Back to top]
Recent Advances in the Development of Adenovirus and Poxvirus-Vectored
Tuberculosis Vaccines
Zhou Xing, Michael Santosuosso, Sarah McCormick, Teng-Chih
Yang, James Millar, Mary Hitt, Yonghong Wan, Jonathan Bramson
and H. M. Vordermeier
Tuberculosis vaccine research began with the search for a
vaccine that might be better than, and thus could replace,
the current Bacillus Calmette Guérin (BCG) vaccine.
Over the last fifteen years or so, intense research effort
has led to the identification of a number of novel tuberculosis
(TB) vaccines which can be divided into 4 categories: genetically
modified mycobacteria, protein, plasmid DNA and viral. However,
it is increasingly believed that the current BCG vaccine will
continue to be used as a childhood vaccine and that more effort
should be directed to developing ap-propriate boosting vaccines.
Mounting evidence suggests that recombinant genetic vaccines,
particularly recombinant viral vaccines, are effective in
boosting immune activation and protection by BCG vaccination.
Since modified vaccinia virus Ankara (MVA)- and adenovirus-vectored
TB vaccines have been most extensively studied, this review
will focus on recent advances in the development and applications
of these two viral TB vaccines.
[Back to top]
Animal Models for Growth Hormone Gene Therapy
Cibele N. Peroni, Peter W. Gout and Paolo Bartolini
Treatment of growth hormone (GH) deficiency via
parenteral administration of recombinant hGH has greatly benefited
from recombinant DNA technology allowing production of practically
unlimited amounts of the pure hormone. However, an alternative
approach that may lead to correction of the clinical defect
is presented by hGH gene transfer into somatic cells of the
patient, either ex vivo or in vivo. This
approach has not only the potential advantage of circumventing
repetitive injections of the hormone and its laborious isolation
and purification processes, but can also, in principle, provide
a mechanism of hormone delivery that resembles the natural
process. GH gene therapy has not reached the clinics yet,
but several interesting and promising animal models for this
treatment have been developed and studied. They are not only
potentially useful for elucidation of the still unresolved
mechanism of sustained in vivo gene product delivery,
but also for opening the way to therapy of other protein deficiencies
for which gene therapy may be the only vi-able option. This
review article describes, analyzes and compares the major
animal models of GH gene therapy that have been developed
in the last two decades.
[Back to top]
Genetic Idiotypic and Tumor Cell-Based Vaccine Strategies
for Indolent Non Hodgkin’s Lymphoma
Pier A. Ruffini, Massimo Di Nicola, Carmelo Carlo-Stella,Salvatore
Siena and Alessandro M. Gianni
B cell malignancies express a clear tumor-specific antigen
(B cell immunoglobulin variable regions) known as idiotype
(Id). It is now possible to immunize patients against autologous
Id generating humoral and cellular immune responses that correlate
with clinical and molecular remissions and the possibility
of improved disease-free survival. In its present form, however,
individual vaccine preparation by generating heterohybridomas
is a technical and financial challenge. DNA vaccination provides
a unique opportunity to streamline individual vaccine manufacture
by circumventing the need for protein purification. DNA fusion
vaccines have been developed in which genetic carriers promote
adaptive immunity against the attached Id. Such carriers can
specifically bind receptors on dendritic cells (DC) for targeted
antigen delivery, or supply high levels of T cell help. Ideally,
the carrier should be able to activate innate immunity to
enhance the antigen-presenting capacity of DC. The correlates
of immunity may vary depending upon the genetic carrier used.
Translation to patients has begun with preliminary evidence
of Id-specific immune responses.
An alternative vaccination strategy that allows for the potential
to vaccinate against multiple tumor antigens without the need
to identify individual antigens is based on tumor cells themselves
to be used as vaccine. To this purpose, however, each patient's
tumor cells must be genetically modified to increase their
immunogenicity. To overcome the technical limitations inherent
with a fully autologous approach, strategies have been devised
where a universal, genetically modified bystander cells is
expected to provide the immunoenhancing cytokines to allow
immune recognition of unmodified patients' tumor cells.
[Back to top]
Immune Response to Herpes Simplex Virus and
γ134.5
Deleted HSV Vectors
Eeva K. Broberg and Veijo Hukkanen
Herpes simplex virus (HSV) is a large DNA virus with unique
properties that can be exploited for in vivo gene therapy.
HSV is neurotropic, establishes latency, and has a large transgene
capacity. These properties can be utilized in therapy of nervous
system diseases. Wild-type HSV and the vectors derived from
it induce both innate and acquired immune response. However,
HSV is skillful in escaping the host response. It has evoked
mechanisms including avoidance of antigen presentation on
major histocompatibility (MHC) molecules, inhibition of host
interferon response, impairment of the antibody and complement
responses, and inhibition of apoptosis in infected cells.
One of the molecules affecting the interferon response is
ICP34.5, encoded by the so-called neurovirulence gene γ134.5.
The mutants deleted of this gene are non-neurovirulent, having
ca 3000-fold decreased ability to replicate in CNS. The HSV
vectors based on the γ134.5
deletion mutants show efficacy against glioma and in other
cancer therapies. These mutants provide an interesting platform
for developing safe and efficient gene delivery for numerous
neurological diseases or brain tumors. The immune response
evoked by the HSV vector is central in determining the spread
and persistence of the vector, and its transgene expression,
and in controlling the innate and adaptive immune response
against effective spread of the vector. These questions are
key issues of herpesviral gene therapy and cancer therapy
at the moment. This review describes the involvement of immune
response in HSV infection and in γ134.5
deletion HSV-based virotherapy. We discuss the challenge of
developing vectors with desired immune response benefiting
the therapy and maintaining the efficiency.
[Back to top]
Erratum
This is with reference to the article entitled, “Altering
the Tropism of Lentiviral Vectors Through Pseudotyping”,
by James Cronin, Xian-Yang Zhang and Jakob Reiser”,
published in Current Gene Therapy, August 2005, Vol. 5, No.
4, pp. 387-398.
The authors unintentionally omitted to include the references
listed below in the reference section of the article:
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