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More news on AAV trial death

The report on the NIH RAC meeting discussing the death of the patient during a clinical trial of an AAV vector has been published, and can be found in the link below. Links are also provided to comments on the case which were recently published in Nature and Nature Medicine. In one of the articles, doctors and scientists are quoted who criticize the design of the trial.
AAV death poor trial design
AAV death RAC meeting
AAV death therapy on trial
Nature comment


Update on death of patient in AAV-vector trial

It has been revealed that the patient who recently died while taking part in a clinical trial of an AAV vector-based anti-arthritis treatment was infected with a fungus that usually causes only a mild illness and a cold-sore virus which is normally kept in check by the immune system, but which had both spread throughout her body, suggesting that her immune system was seriously impaired. This may be related, however, to the fact that she was also taking conventional immune-suppressing drugs for her arthritis. A link to the news item, and a recent article in Science about the case can be found below:

article in Science

New setbacks in gene therapy trials

Two further adverse events in gene therapy clinical trials have recently been reported.

A patient in the clinical phase I trial to treat X-SCID sufferers performed at the Necker hospital in Paris has developed a leukemia-like disease, about 5 years following treatment. This is the fourth patient to develop such a condition in this trial, and means that half of the patients who were successfully treated have gone on to experience this adverse side-effect. However, in a similar trial performed in London, no adverse events have yet been observed, indicating that protocol-specific differences in the trials may be critical determinants in the genotoxicity profile of this therapy.

The ESGCT released a statement to this case and an editorial in Molecular Therapy was also published.

In an unrelated clinical trial, using an AAV vector to treat arthritis, a patient died in a clinical trial following a second administration of the vector, which was designed to express Tumor Necrosis Factor Receptor. This trial has been placed on hold, and all related trials involving AAV vectors are being investigated by the FDA. The cause of death of the patient has as yet not been established, however, and hence it is not known if it was related to the gene therapy. Links to the FDA statement and news items can be found below:


Latest news in the debate on gene therapy of SCID

In April of this year, Niels-Bjarne Woods et al. published a brief communication in Nature (link to Woods et al. pdf), where they presented data which they claimed demonstrated that the therapeutic gene used to treat X-SCID in human gene therapy trials (IL2RG) is oncogenic when overexpressed via a lentiviral vector in a murine model of X-SCID. This is an important finding, since three out of a total of 20 human patients treated with this gene (albeit using a retroviral vector) developed clonal T-cell leukemia. Arising from this publication, two further articles appeared in Nature in September of this year, both of which challenge the findings of Woods et al.. Karin Pike-Overzet et al. (link to Pike-Overzet et al. pdf) find that overexpression of the IL2RG gene does not affect T-cell development, and propose that it is not directly oncogenic, but that it its overexpression could contribute indirectly to oncogenesis by allowing the normal progression of T-cell development that are permissive for the pro-leukemic effects of genuine oncogenes such as LMO2. Thrasher et al.  also present the results of experiments in which human IL2RG was expressed in mice and in which none of the animals developed tumours. Both Pike-Overzet et al. and Thrasher et al. also argue that there are fundamental differences in the T-cell development between mice and humans, and that care must be taken in attempting to extrapolate the results of murine studies to having relevance in a human setting. In the same issue, Woods et al. reply to both of these criticisms, emphasizing that their intention was only to warn that IL2RG, when overexpressed in some settings, has the potential to be oncogenic, and that their results should in no way stimulate drastic changes in currently successful gene therapy protocols. Their major point remains, however, that the expression  of IL2RG (and, by extrapolation of all transgenes) used in gene therapy should, if possible, not exceed physiological levels.

Related to this debate, Shou et al. recently published an article (link to Shou et al. pdf) investigating the risk factors for insertional mutagenesis in a mouse model of X-SCID gene therapy, and Buchholz and Cichutek (link to Buchholz et al. pdf) published a commentary dedicated to the ongoing debate as to whether clinical trials should still go ahead using conventional retroviral vectors, or whether the use of self-inactivating (SIN) vectors should become standard)

Finally, a second publication from the Thrasher group documents the successful gene therapy of ADA-SCID (link to Gaspar et al. pdf).


Report on the Life Sciences 2006 meeting

The ANGT took part in the annual meeting in Salzburg from September 25th to 27th, along with the other Austrian societies representing the Life Sciences.

The Gene Therapy session was a resounding success, with a blend of established, internationally renowned scientists and young home-grown talent providing insights into various aspects of gene therapy from the research bench to clinical application.

The session was opened with the Austrianova Gene Therapy Lecture, which was this year delivered by Professor Srinivasan Chandrasegaran from the John Hopkins University in Baltimore, USA. He is the founding father of the highly promising Zinc Finger Nuclease (ZFN) technology and gave an excellent talk taking the audience on a journey from the very early days of his discovery through to potential future applications such as gene therapies for X-SCID and HIV.

This plenary lecture was followed by a short talk from Dr. Sundar Durai from Pondicherry University in India, who continued in the ZFN vein by presenting his work on systems for the high-throughput selection of functional Zinc Finger Proteins (ZFPs), which can then be used for the generation of novel ZFNs.

The second short talk was given by Dr. Karoline Lipnik from the University of Veterinary Medicine in Vienna, Austria, who shared her latest findings on the novel anti-tumour effects of the human guanylate binding protein (GBP)-1.

This was then followed by the really stimulating plenary lecture of Stefano Ferrari from the Veneto Eye Bank Foundation in Venice, Italy, which demonstrated the power of stem cells to regererated skin and eye injuries, and how a combination of the advances in tissue engineering, stem cell technology and the application of gene therapy to keratinocyte stem cells could produce a future therapy for Epidermolysis Bullosa (EB).

The session was wrapped up by a short talk from another homegrown “Nachwuchsforscher”, Irene Pfaffenzeller from the University of Natural Resources and Applied Life Sciences (BOKU) in Vienna, Austria, who shared the insights which she has gained from her work on the development of antibiotic-free plasmid production techniques, which could have far-reaching implications for gene therapy using non-viral delivery of the therapeutic gene.

Ark begins marketing authorisation application for glioma gene therapy product

London, UK, 1 September 2006 - Ark Therapeutics Group plc ('Ark' or the 'Company') today announces that it has filed its response to the first series of questions raised by the EMEA's scientific committee as part of the marketing authorisation application (MAA) review process for Cerepro(TM), its novel gene-based medicine for the treatment of operable high grade glioma (brain cancer). Ark's response has been filed in accordance with the standard procedure and time frame. The application for marketing approval was submitted by Ark in the second half of last year and, following validation of the submission by the EMEA, was accepted for review in October 2005.

To facilitate the response, Ark's Finnish manufacturing facility has manufactured the necessary 'conformity' batches of Cerepro(TM) to commercial supply specifications. The Phase II Cerepro(TM) study, which forms the main clinical evidence in the submission, has also been subject to a GCP inspection as a specific part of the MAA review process. In addition, Ark's headquarters has satisfactorily completed a full good clinical practice ('GCP') system inspection under the new EU pharmaceutical regulations.

Cerepro(TM) has completed three clinical studies during its development to date: a Phase I study establishing safety and posology (dosing and method of administration) and two safety and efficacy studies. Cerepro(TM) treatment produced an average extension of 7.5 months of life, almost doubling survival time in a disease where most patients will only live for around eight months.

Cerepro(TM) has Orphan Drug Status in Europe and the USA and is the first gene medicine in the world (1) to undergo a formal MAA review.

Dr Nigel Parker, CEO of Ark, commented: 'This review is significant because it gives clarity to the regulatory requirements and standards that need to be met for gene-based medicines, a new and exciting class of biological drugs in which Ark is rapidly becoming recognised as a world leader. We continue to make significant advances with Cerepro(TM) and look forward to providing further updates on its overall progress in due course.'

Notes (1) ex-China

Life Sciences 2006, Salzburg, September 25th- 27th

The ANGT is again teaming up with the other Austrian life-sciences based societies (ÖGBM, ÖGGGT and ÖGBT) to take part in the 2006 Life Sciences meeting, which will be held at the University of Salzburg from the 25th to the 27th of September. Invited speakers working in the field of gene therapy will include Srinivasan Chandrasegaran (USA) and Michele De Luca (Italy). This meeting will also provide Austrian scientists with the chance to present their work , both in oral and poster presentation formats. Abstracts can be submitted until the 10th of July, and registration for the meeting at a reduced fee is possible until August 28th. More information can be found on the meeting homepage using the following link:

The results of a clinical trial published

The results of a clinical trial published in the April edition of Nature Medicine provides a novel insight into the role of retroviral insertional mutagenesis in gene therapy. Until now, the activation of non-target genes due to the random nature of integration has always been viewed as an unavoidable and purely negative side effect of using retroviruses as gene therapy vectors. This new study, which has apparently cured two adult men from the rare immunodeficiency, chronic granulomatous disease (CGD), however, indicates that the serendipitous activation of genes that promoted proliferation and differentiation of the treated cells played an important role in the success of the trial. The original paper can be downloaded here , and an editorial on the subject published in the same journal can be downloaded here.

Gene therapy and oncolytic viral therapy products approved in China
The Chinese State Food and Drug Administration (SFDA) has approved H101, an oncolytic adenovirus, to be used in combination with chemotherapy as a treatment for patients with late stage refractory Nasopharyngeal cancer, a type of head and neck cancer prevalent in China. This marks the first oncolytic viral therapy approved by any regulatory agency in the world.
An editorial on this subject from the Feb 2006 issue of "Molecular Therapy" can be viewed here.
This came hot on the heels of the approval by the SFDA of Gendicine, an adenoviral vector expressing the wild-type p53 gene for the treatment of head and neck squamous cell carcinoma, which is the first ever commercially approved gene therapy product worldwide.
Editorial and review articles on this subject from the Sep 2005 issue of "Human Gene Therapy" can be viewed here:  gendicine editorial and gendicine in china