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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