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Report
on the ANGT meeting in Vienna, 26th to 28th of September 2005
From the 26th to the 28th of September, the ANGT worked together with the
other Austrian life-sciences based societies (ÖGBM, ÖGGGT and ÖGBT) to
host the 2005 Life Sciences meeting, which was held this year at the
Unversity of Agricultural Sciences in Vienna. There was an interesting and
successful gene therapy session on Tuesday the 27th of September, the
highlights of which were the plenary lectures given by Andrew H. Baker
(Glasgow), who presented his work on cardiovascular gene therapy, and
Adrian Thrasher (London), who talked about successful gene therapy for
immunodeficiency. Short talks were held by Matthias Paar (Vienna), who
presented his data on the genomic stability of different designs of
replication-competent retroviral vectors and the transcriptional targeting
of these vectors, and Petra Haag (Innsbruck), who presented her work on
the in vitro and in vivo delivery of androgen receptor antisense
oligonucleotides with microbubble enhanced ultrasound. Several other very
interesting abstracts could not be chosen for talks, but the authors
presented their data at the meeting in poster format. Next year, the
meeting will be held in Salzburg.
Report
on the 28th Seminar of the Austrian Society for Surgical
Research in Gosau, December 8th to 10th 2004
The
Austrian Society for Surgical Research (http://www.kfunigraz.ac.at/chiwww/ChirFor/)
held their annual seminar in the beautiful ski resort of Gosau in the
Salzburg mountains. They generally have a different topic of focus each
year and in 2004 it was turned to gene therapy. Physicians active in
several fields including cardiovascular research, cartilage repair,
anti-tumour vaccination, cytokine treatment of tumours, burn treatment,
and granulomatosis were present, and a delegation of biologists presented
their work on cell-based therapy of pancreatic and mammary tumours. The
presence of researchers with experience at many different stages of the
gene therapy “production line” (from basic vector design and
optimisation, through product development and clinical trial design to
practical application in a clinical setting) stimulated a series of lively
and informative discussions, and the exchange of ideas and information was
beneficial to all parties. It is hoped that this meeting was just the
beginning of a long future of co-operation between scientists and
physicians working on gene therapy in Austria.
Report
on ANGT meeting in Innsbruck 20-22 September 2004
As part of
the joint annual meeting with the other austrian life sciences societies
(ÖGBM, ÖGGGT and ÖGBT), the ANGT hosted an interesting and successful
gene therapy session on Tuesday 21st September. The session was opened
with the Austrianova Gene Therapy Lecture which was provided this year by
Dr. Dirk Nettelbeck who is currently based at the Department of
Dermatology at the University Clinic in Erlangen, Germany, specialising in
the treatment of melanoma with targeted, replication competent
adenoviruses. Further talks were held by Chukwuma Agu, who presented data
from his work with a novel toxic gene which has great potential for cancer
gene therapy applications, and Verena Wally, who gave an overview of her
results achieved using spliceosome mediated mRNA trans-splicing (SmaRT)
technology for the therapy of plectin deficient epidermolysis bullosa.
There were also several other very interesting abstracts whose authors
were unable to present their data in a talk format due to time
constraints, but which contributed to two stimulating poster sessions. All
in all, the meeting was a great success for all participants, and we are
already looking forward to next autumn when the meeting will be held in
Vienna.
Boost
for Austrian biotech company
The
Vienna-based biotech company Austrianova was recently given a positive
decision from the European Medicines Evaluation Agency (EMEA) which will
ensure that data generated in an upcoming phase III trial of their cell
therapy of pancreatic cancer can be used for market authorization,should
the trial be successful. The trial, which will compare the efficacy of
locally-implanted capsules containing ifosfamide-converting cells to
gemcitabine treatment, which is the current standard therapy, will begin
in 2005 and will involve around 200 patients from several clinical centres
in Europe.
For
more information see http://www.austrianova.com
AAV
trial halted
A trial of a highly promising
gene therapy approach to the treatment of hemophilia has been put on hold
because two of the seven patients involved in the trial developed mild
side effects, most likely due to an immune response mounted against the
adeno-associated viral vector, which did not arise during a successful
trial in dogs. The safety problem is minor, however, and the researchers
involved are hoping to continue the trial following modification of the
vector and / or treatment protocol. This development also highlights the
very important point that, until a gene therapy protocol is actually put
through clinical trials, it is impossible to be sure how human patients
will respond to the treatment, regardless of the results of animal
testing.
click
here for the PDF
SCID
trials to resume
The French gene therapy trial
for X-linked SCID, led by Alain Fischer of the Necker Hospital in Paris,
is set to restart following a 22 month suspension. Scientists have gained
more knowledge about the reasons why 2 patients developed leukemia as a
result of treatment (both of whom are recovering from their cancers), and
it has been decided that the benefits of treating patients outweigh the
risks posed to them in this particular case. Moreover, future trials will
minimize risks by only treating children older than six months, and
limiting the number of corrected cells which are reintroduced to the
patients.
click
here for the PDF
Promising news for
retroviral gene therapy
A
recent publication in Science magazine has provided some revealing and
potentially reassuring insights into the mechanism of insertional
tumorigenesis observed in 2 out of 10 patients who received gene therapy
for SCID-XI. Both of these patients were found to have a clonal T-cell
leukemia in which the retroviral vector used for therapy was integrated in
the proximity of LMO2, a known
human oncogene. The authors screened a database of over 3000 integration
sites in retrovirally induced murine haematopoietic tumours. They
identified one tumour containing integrations at both LMO2
and Il2rg, the locus which
produces the
gc
chain of the cytokine receptor, which is the product of the therapeutic
gene used to treat these SCID-XI patients. Since there is only a minute
probability of a tumour having integrations at both these loci by pure
chance, the authors conclude that this provides evidence for a
cooperativity between the two genes in tumorigenesis. Although gc
is upregulated neither in the leukemias of the SCID-XI patients nor in
that of the mouse, the authors suggest that other, more subtle expression
effects could be responsible for its observed oncogenicity. Since,
however, most of the SCID-XI patients treated did not develop leukemia,
but can all be expected to have an integration in vicinity of the LMO2
locus (due to the large numbers of cells initially infected), it seems
that additional factors must also play a significant role in
tumorigenesis. The authors conclude that this new information, in addition
to the fact that although this trial is only one of many which have taken
place during the last several years it is the only one in which
insertional tumorigenesis has been observed, strongly suggests that only
in rare cases where the therapeutic gene also has oncogenic potential will
insertional tumourigenesis occur as a result of retroviral gene therapy. click
here for the PDF
First Christian Doppler
Laboratory for Gene Therapeutic Vector Development
The first Christian Doppler laboratory dedicated to gene therapy and
vector research was opened on December 1st, 2003. To celebrate this, an
international symposium was held at the University of Veterinary Medicine
on January 22-24th, 2004 and included presentations by Nori Kasahara,
David Klatzmann and Finn Skou Pedersen. The new Christian Doppler
Laboratory is co-financed by Austrianova
and Sanochemia.
Salzburger
Nachrichten
Recent Important Milestones
in Gene Therapy
A number of important milestones have been reached in the area of gene
therapy over the last few months.
These include:
1) the first clinical use of lentiviral vectors based on HIV by the US
company VIRxSYS for the treatment of HIV infections in July, with safety
data already being presented in September. http://www.virxsys.com/DSMBPressRelease090403.pdf
2) FDA approval for a clinical trial involving the first systemically
delivered, infection targeted retrovirus in August. Epeius Biotechnologies
(US) is using the vector to deliver cyclin G1 as a therapuetic gene for
the treatment of pancreatic cancer. http://www.epeiusbiotech.com/home.html
3) the first gene therapy product to receive market approval (November).
This is an adenovirus vector carrying the p53 gene to treat head and neck
cancer. Approval was granted to SiBiono GeneTech of Shenzen, Guangdong
Province, China for their product, Gendicine, which is produced using New
Brunswick Scientific's CelliGen® Plus bioreactor. http://www.nbsc.com/
This and other encouraging news (including data presented at the recent
Cordia event in Vienna) resulted in a recent lead article in the trade
magazine "Genetic Engineering News" entitled "Promise of
successful gene therapy resurges" published in the November 15, 2003
edition. http://www.genengnews.com/
GENE THERAPY IN PUBLIC DEBATE
Preferential sites of integration for viral vectors revisited
Recent publications open up the debate about preferred integration sites
for virus vectors based on AAV, lentiviruses and retroviruses. More
information can be found at:
http://www.vetscite.org/cgi-bin/pw.exe/Issue4/news/001208.htm
Third patient with integration at Lmo2 locus without leukaemia suggests
other events are required
In the March 15th issue of New Scientist, p6, the following was reported:
DESPITE its spectacular achievements, the first successful form of gene
therapy will for now be used only as a last resort due to the risk of
cancer. And that's not the only bad news. The latest studies suggest that
some other gene therapies using different viruses might also trigger
cancer. The Necker Hospital in Paris pioneered the use of gene therapy to
cure the severe inherited immune disease called X-SCID. But two of the 11
boys treated have developed leukaemia. Both these cases appear to be due
to the corrective gene being inserted near another gene called Lmo2, which
helps control cell growth and can contribute to cancer if turned on at the
wrong time (New Scientist, 25 January, p 12).
Calculations by Christof von Kalle of the University of Cincinnati College
of Medicine in Ohio suggest that rather than being an extraordinary
coincidence the engineered mouse retrovirus used to deliver the gene in
the French studymay insert it near Lmo2 about once per 100,000 insertions.
Since millions of bone marrow cells are modified and returned to the boys,
such insertions may crop up in most if not all of the patients.
The added gene has now turned up near Lmo2 in a third child in the French
trial, von Kalle last week told a gene therapy conference in Banff,
Canada. Fortunately, the boy shows no signs of leukaemia, suggesting that
a further genetic defect may be necessary to trigger uncontrolled growth
of the modified cells.
Gene therapists are still hoping that this problem will prove specific to
the gene or methods used in the X-SCID therapy. But experiments done by
Frederic Bushman of the Salk Institute near San Diego suggests there could
also be a potential problem with HIV and other related retroviruses, which
many researchers are planning to use in gene therapy.
Bushman infected human cells with the viruses and looked to see where they
landed. Last year, he reported that the viruses are more likely to land in
genes- especially in active ones- than in the regions between genes.
Now it seems the viruses prefer to land in genes that can trigger cancer
if wrongly switched on or off. Of 440 viral insertions into genes, 5 per
cent occurred in known "oncogenes", even though these make up
only 1.6 per cent of all genes, he told the conference.
"It looks like we're seeing a significant bias in favour of insertion
into oncogenes," says Bushman. "This is potentially not the
greatest news." However, he stresses that no one yet knows whether
these insertions turn oncogenes on or off, or indeed have any effect on
them at all.
Despite these findings, most gene therapists remain optimistic. "I
don't think this signals the end of the retrovirus [in gene
therapy]," says Michel Sadelain of the Sloan-Kettering Cancer Center
in New York. "There are things that one can do to reduce the
risk." This includes modifying viruses so they insert genes only in
specific sites in the genome, or adding self-destruct mechanisms so
doctors could kill the altered cells if any went awry, says Sadelain.
In the meantime, an FDA advisory committee last week recommended that 27
suspended gene therapy trials should proceed only if gene therapy is the
only option. Similarly, Great Ormond Street Children's Hospital in London
will treat X-SCID boys only if "death is otherwise inevitable".
The French trial remains on hold.
Serious Adverse Event in a Gene Therapy Clinical Trial
A second case of a serious adverse event has been reported from the
clinical trial for the treatment of X-linked severe combined
immunodeficiency. For more information as well as statements from the
principle investigator and the the European Society for Gene Therapy
please follow this link: http://www.esgt.org/
The Paul-Ehrlich-Institute, German Federal Agency for Sera and Vaccines
has also recently released a statement about the trial under the title
"Entscheidung der Kommission Somatische Gentherapie: Einige der
unterbrochenen Gentherapie-Studien mit retroviralen Vektoren können
weitergeführt werden" at: http://www.pei.de/
MEETING REPORTS
Report of the 2002 Meeting on Gene Therapy (Annual ANGT Meeting), held in
Salzburg, Austria in September 2002 Report (LINK)
The abstracts for the 6th Annual Meeting of the American Society of Gene
Therapy are available in Molecular Therapy Volume 7, Issue 5, Supplement
1. This issue is available on ScienceDirect. The abstracts are also
available at the following site, along with more detailed search
instructions: http://208.164.121.55/ASGTupdates/
MEETINGS
The Austrian Society for Biochemistry and Molecular Biology (ÖGBM),
the Austrian Society for Genetics and Gene Technology (ÖGGGT),
the Austrian Society for Biotechnology (ÖGBT) and
the Austrian Network for Gene Therapy (ANGT)
will hold their Annual Meeting
from 22nd to 24th September 2003 at the RESOWI-Center of
Karl-Franzens-University in Graz (Universitätsstrasse).
Online registration: www.bcc.univie.ac.at/ogbm/Meeting/ogbm1.htm
The 11th Annual Meeting of the European Society of Gene Therapy,
dedicated to the development of gene therapy, cell therapy and genetic
vaccines will be held at the Edinburgh International Conference Centre,
November 14-17, 2003. More information and registration details can be
obtained at http://217.215.32.12/esgt/index.html
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