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Current
Gene Therapy
ISSN: 1566-5232
Current Gene Therapy
Volume 7, Number 3, June 2007
Contents
Advances in the Treatment of Chronic Granulomatous
Disease by Gene Therapy Pp. 155-161
Marion G. Ott, Reinhard Seger, Stefan Stein, Ulrich Siler,
Dieter Hoelzer and Manuel Grez
[Abstract]
On the Search for Skin Gene Therapy Strategies
of Xeroderma Pigmentosum Disease Pp. 163-174
Carlos F.M. Menck, Melissa G. Armelini and Keronninn M.
Lima-Bessa
[Abstract]
Genomic Context Vectors and Artificial Chromosomes
for Cystic Fibrosis Gene Therapy Pp. 175-187
Massimo Conese, A. Christopher Boyd , Sante Di Gioia,
Cristina Auriche and Fiorentina Ascenzioni
[Abstract]
Current Advances and Future Challenges in Adenoviral
Vector Biology and Targeting Pp. 189-204
Samuel K. Campos and Michael A. Barry
[Abstract]
Development of Ribozyme-Based Gene-Inactivations;
The Example of the Hepatitis Delta Virus Ribozyme
Pp. 205-216
M. Asif-Ullah, Michel Lévesque, Gilles Robichaud
and Jean-Pierre Perreault
[Abstract]
Perspectives for Gene Therapy of Wilson Disease
Pp. 217-220
Uta Merle, Wolfgang Stremmel and Jens Encke
[Abstract]
Gene Therapy in Peripheral Nerve Reconstruction Approaches
Pp. 221-228
Kirsten Haastert and Claudia Grothe
[Abstract]
Abstracts
[Back to top]
Advances in the Treatment of Chronic Granulomatous Disease
by Gene Therapy
Marion G. Ott, Reinhard Seger, Stefan Stein, Ulrich Siler,
Dieter Hoelzer and Manuel Grez
Gene transfer into hematopoietic stem cells has been
successfully used to correct immunodeficiencies affecting
the lymphoid compartment. However, similar results have not
been reported for diseases affecting myeloid cells, mainly
due to low engraftment levels of gene-modified cells observed
in unconditioned patients. Here we review the developments
leading to a gene therapy approach for the treatment of Chronic
Granulomatous Disease (CGD), a primary life threatening immunodeficiency
caused by a defect in the oxidative antimicrobial activity
of phagocytes. Although the disease can be cured by bone marrow
transplantation, this treatment is only available to patients
with HLA-identical sibling or matched unrelated donors. One
therapeutic option for patients without suitable donor is
the genetic modification of autologous hematopoietic stem
cells. Although early attempts to correct CGD by gene therapy
were unsuccessful, these studies demonstrated the safety and
limitations of gene transfer into hematopoietic stem cells
(HSC) of CGD patients using retroviral vectors. The recent
development of advanced gene transduction protocols together
with improved retroviral vectors, combined with low intensity
chemotherapy conditioning, allowed partial correction of the
granulocytic function with a significant clinical benefit
in treated patients. These results may have important implications
for future applications of gene therapy in myeloid disorders
and inherited diseases using hematopoietic stem cells.
[Back to top]
On the Search for Skin Gene Therapy Strategies
of Xeroderma Pigmentosum Disease
Carlos F.M. Menck, Melissa G. Armelini and Keronninn M.
Lima-Bessa
The introduction of genes through the skin has been an attractive
and dynamic field of research in recent years. It gives the
first gleam of hope in therapy for the human genetic diseases
that mainly affect this tissue, such as patients that suffer
from xeroderma pigmentosum, and who experience increased frequency
of skin cancer. The first in vitro experiments were
successful in correcting the genetic defects of cells from
these patients, the ex vivo reconstruction of corrected
cells has been achieved, and the skin of model animals has
been treated resulting in cancer prevention. Up to now these
efforts have been possible, thanks to the high efficiency
of viral vectors that provide gene delivery and expression
targeted to many of the different skin cells, including those
with proliferative and pluripotent features, such as keratinocytes
and epidermal cells of hair follicles. Moreover, progress
with several other methodologies qualifies them as alternatives
to be explored, in some cases in combination with viral vectors,
for skin gene therapy in these patients. Exciting and encouraging
new approaches promise benefits to xeroderma pigmentosum patients
and their families, and open perspectives of new ways for
interfering in gene driven metabolism in the skin.
[Back to top]
Genomic Context Vectors and Artificial Chromosomes
for Cystic Fibrosis Gene Therapy
Massimo Conese, A. Christopher Boyd , Sante Di Gioia,
Cristina Auriche and Fiorentina Ascenzioni
Cystic fibrosis (CF) is caused by mutations of the CF transmembrane
conductance regulator (CFTR) gene, which encodes a cAMP dependent
chloride channel whose expression is finely tuned in space
and time. Gene therapy approaches to CF lung disease have
demonstrated partial efficacy and short-lived CFTR expression
in the airways. Drawbacks in the use of classical gene transfer
vectors include immune response to viral proteins or to unmethylated
CpG motifs contained in bacterially-derived vector DNA, and
shut-off of viral promoters.
These limitations could be overcome by providing stable maintenance
and expression of the CFTR gene inside the defective cells.
This strategy makes use of large fragments of DNA of various
sizes containing the CFTR transgene and its relevant regulatory
regions, (genomic context vectors [GCVs], reaching ultimate
complexity in the form of an artificial chromosome [AC]) as
vector for the transgene. Appropriate regulation in space
and time would be achieved by the presence of the endogenous
promoter and other control elements, while retention in daughter
cells could be ensured by the presence of sequences which
guarantee episomal replication.
In this review, we describe recent advances in GCVs and ACs
and the technology underlying their construction. These vectors
have been shown to be suitable for delivery and expression
of therapeutically relevant genes, including CFTR. The major
issue which now limits their routine use is delivery inefficiency.
Once this issue is resolved, we will be closer to achieving
the goal of regulated gene therapy for CF.
[Back to top]
Current Advances and Future Challenges in Adenoviral
Vector Biology and Targeting
Samuel K. Campos and Michael A. Barry
Gene delivery vectors based on Adenoviral (Ad) vectors have
enormous potential for the treatment of both hereditary and
acquired disease. Detailed structural analysis of the Ad virion,
combined with functional studies has broadened our knowledge
of the structure/function relationships between Ad vectors
and host cells/tissues and substantial achievement has been
made towards a thorough understanding of the biology of Ad
vectors. The widespread use of Ad vectors for clinical gene
therapy is compromised by their inherent immunogenicity. The
generation of safer and more effective Ad vectors, targeted
to the site of disease, has therefore become a great ambition
in the field of Ad vector development. This review provides
a synopsis of the structure/function relationships between
Ad vectors and host systems and summarizes the many innovative
approaches towards achieving Ad vector targeting.
[Back to top]
Development of Ribozyme-Based Gene-Inactivations;
The Example of the Hepatitis Delta Virus Ribozyme
M. Asif-Ullah, Michel Lévesque, Gilles Robichaud
and Jean-Pierre Perreault
The development of gene-inactivation systems is an active
and important field for both functional genomics and gene
therapy. Towards this end, ribozymes (i.e. RNA enzymes), that
specifically recognize and subsequently catalyze the cleavage
of other target RNA molecules, are attractive molecular tools.
Ribozymes represent an interesting alternative to the RNA
interference (RNAi) approach for gene inactivation, especially
given the fact that RNAi seems to trigger an immunological
response and has demonstrated off-target effects. However,
the design and optimization of a ribozyme-based gene-inactivation
system is not a straightforward procedure. Several aspects
need to be considered in the experimental design in order
to provide a suitable suppression system. In this review we
present the advances in this domain made available from work
using the hepatitis delta virus (HDV) ribozyme as a cis-acting
RNA motif in molecular biology, as well as a trans-acting
molecular scissor for the development of a gene-inactivation
system. This HDV ribozyme technology possesses several unique
features that are all related to the fact that it is the only
catalytic cleaving RNA motif that has been discovered in humans.
[Back to top]
Perspectives for Gene Therapy of Wilson Disease
Uta Merle, Wolfgang Stremmel and Jens Encke
Wilson disease is a rare autosomal-recessive copper overload
disorder due to mutations of the Wilson disease gene ATP7B.
The disease typically manifests at late childhood or in young
adults with hepatic and/or neurological symptoms. Being fatal
without medical treatment or liver transplantation the long-term
outcome of Wilson disease depends on the adherence to an effective
treatment. Because current medical treatment options are not
effective in all Wilson disease patients and adherence to
therapy is a problem, gene therapy might represent an alternative
curative future therapy. In the rat model of Wilson disease
adenoviral and lentiviral gene transfer studies could prove
that viral gene transfer is therapeutically effective and
can reverse clinical symptoms. However, both approaches were
limited by a more or less transient transgene expression.
As several tactics can be used to overcome these current limitations,
gene therapy approaches may become more efficient than standard
medical treatment for Wilson disease in the future. This review
discusses both, existing vectors and strategies and prospective
developments towards liver-directed gene therapy, although
there is still a long way to go until gene therapy can be
used for safe treatment of Wilson disease in humans.
[Back to top]
Gene Therapy in Peripheral Nerve Reconstruction Approaches
Kirsten Haastert and Claudia Grothe
Gene transfer to a transected peripheral nerve or
avulsed nerve root is discussed to be helpful where neurosurgical
peripheral nerve reconstruction alone will not result in full
recovery of function. Axonal regeneration is supposed to be
facilitated by this new therapeutic approach via
delivery of specific regeneration promoting molecules as well
as survival proteins for the injured sensory and motor neurons.
Therefore gene therapy aims in long-term and site-specific
delivery of those neurotrophic factors. This paper reviews
methods and perspectives for gene therapy to promote functional
recovery of severely injured and thereafter reconstructed
peripheral nerves. Experimental in vivo and ex
vivo gene therapy approaches are reported by different
groups. In vivo gene therapy generally uses direct
injection of cDNA vectors to injured peripheral nerves. Ex
vivo gene therapy is based on the isolation of autologous
cells followed by genetic modification of these cells in
vitro and re-transplantation of the modified cells to
the patient as part of tissue engineered nerve transplants.
Vectors of different origin are published to be suitable for
peripheral nerve gene therapy and this review discusses the
different strategies with regard to their efficiency in gene
transfer, their risks and their potential relevance for clinical
application.
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