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(text by S. Rusconi)
Fw: You will find further basic informations about gene technology in the dossier prepared by V Cottier and F. Guerry (in French)
What is 'gene therapy'?
Since more than 15 years genes are employed to biotechnologically produce pure proteins that are used as bio-pharmaceuticals (insulin, growth hormone, blood clotting factors, erythropoietin etc.).
GENE THERAPY is a medical technology in which DNA is directly used as a pharmaceutical. In this technique, genes or fragments thereof are transferred into a human being with the purpose of preventing, treating or healing a disease.
The gene transfer is operated by means of vectors that are either virally or non virally based. The major difficulty in gene transfer is the achievement of a satisfactory efficiency.
Many disorders can be potentially treated with gene therapy: they can be inherited or acquired disorders.
Gene therapy clinical trials started in 1990 and the procedure is still very experimental. As of today, about 200 trials have been conducted which involved about 3000 patients. Also in Switzerland a certain number of trials have been or are being currently conducted.
Further questions and reading:
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viral vectors |
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What means 'somatic' gene therapy?
The term 'somatic' stays in contrast to the term 'germline'. With a germ line gene transfer, the modification of the genome is transmitted to the subsequent generations via the germ cells (spermatozoids, ovules). Since genomic alterations cannot yet be precisely controlled, germ line interventions do not have a biological justification, since they could cause harm to future generations. Furthermore, the alteration of the trasmissible genetic material poses a number of ethical questions. For these reasons, germ line interventions are momentarily forbidden in our country as well as in many other countries.
With the 'somatic' gene transfer, we target only the genetic material of tissues (muscles, lung, brain, bones, kidney, heart etc...) that do not contribute to the hereditary transmission. Therefore, the alteration remains within the treated person. This does not mean that somatic gene alterations are without potential danger. Currently one is actively ascertaining the extent of possible damage that can occur by random insertion of genes into the genome. Depending on the vector and the method used, this risk will be more or less elevated and this parameter will influence the indications and contra-indications of this particular treatment.
Which diseases can be treated with gene-assisted therapy?
Essentially, all forms of diseases can be treated to a variuous degree by altering gene expression. Commonly, one thinks of gene therapy as destined to heal hereditary diseases such as
On top, a large number of diseases that are genetically predisposed, but also depend on external factors can be treated such as:
Finally, also purely accidental (acquired) disorders can be treated with gene transfer such as:
Please contact us, if you wish to receive specific informations about any of the above disease classes and the corresponding gene therapy efforts.
Which vectors for gene transfer are currently considered?
Definition of 'in-vivo' and 'ex-vivo':
We speak of 'in vivo' delivery, when the gene transfer is applied
either locally (for instance intra muscular, intra tumoral injection,
inhalation, local permeation etc.) or systemically (intravenous
injection) to the intact body. We speak of 'ex vivo' delivery when
the gene transfer is performed on cells or tissues that are first
explanted, cultured in the laboratory, then re-implanted into the
patient.
Physical vectors/methods:
the physical methods have a limited application to surface gene transfer or to ex-vivo gene transfer (explanted organs or tissues). The intra-tissue injection is useful only when the therapy does not require abundant expression of the transferred gene (for example when treating patients with VEGF-expressing vectors).
Chemical vectors/methods:
Chemical methods have the advantage of being easy to assemble from defined components, but they are currently between 100- and 1000-fold less efficient than biological vectors. Further Improvements, such as the generation of mixed chemical/biological particles (see below, that is with the inclusion of specific viral proteins) may lead to the generation of the so called 'virosomes' or 'artificial viruses'. The future will tell how efficient those hybrid particles are indeed. We expect virosomes to be 'the' best vectors for in vivo systemic delivery, since they could be engineered to accumulate in the desired body compartment due to their particular docking surfaces.
Biochemical vectors/methods:
In biochemically-based methods, the DNA is complexed with proteins that can enter the cells via natural endocytosis, for instance via receptor-mediated internalisation. They offer the advantage of being specifically targetable to some cells, which is not the case by chemical methods.
Biological vectors/methods (recombinant viruses)
Most of these viruses are engineered to be capable of replicating only in specially engineered cells. Their major advantage is that they can ferry foreign genes at extremely high eficiency. Some of them (example lentiviruses and retroviruses) lead to integration of the genes into the host-genome, permitting permanent transformation. There are of course some safety problems linked with the use of viruses: the first is the accidental emergence of replication competent particles. With the most modern protocols, this problem seems to be under control. Some vectors (such as Adeno) carry intrinsically toxic components (like capsid proteins) and this may preclude their use for mild diseases. Finally, some vectors (such as AAV) do not allow the packaging of long gene sequences, and this is a major limitation for the cure of some disorders like muscular distrophy of cystic fibrosis, where the gene of interest is larger than the available space on the vector. Many efforts are currently devoted to the aim of rendering the vrecombinant viral particles capable of docking at specific surfaces inside the body, such to allow tissue-specific gene transfer upon systemic delivery.
Please contact us if you wish to know more about any of the above mentioned vectors or methods.
Has gene therapy proved its value?
- GT-scepticals use to say that so far Gene
Therapy has only cured mice, in spite of its long history.
Gene therapy clinical trials have officially started in 1990. At that
time a heroic attempt to cure an enzyme defect that causes a severe
immunodeficiency was conducted by FW Anderson and colleagues. Now we
know that the vector used could not guarantee persisting expression
of the transferred gene, therefore we have a rational explanation of
this initial failure. So we can say that GT was probably a
prematurely born baby. However, without those pioneering efforts, we
probably would not have started to put the stones in rolling as it is
now. Therefore, we must pay high respect to the people who had the
courage to implement their vision even if in absence of the
appropriate tools.
- Meanwhile, new and improved vectors have been generated, and a
number of clinical trials has been accomplished. Most of them were at
phase I, where the aim is not to monitor therapeutic effect but to
assess general toxicity. This is the main reason, why we cannot
report a large number of success-stories in humans. In spite of that,
a number of encouraging results has been achieved. For instance, a
direct intra-muscular injection of a gene expressing the vascular
endothelial growth factor (VEGF) was shown by the research team of
Jeff isner (St. Elisabeth Hospital, Boston) to rescue the necrotic
lesions in patients suffering of incurable limb ischemia. Already at
clinical phase I, Dr Isner could spare the amputation on a
substantial fraction of treated patients. those experiments are now
under clinical phase II investigation and one expects further
encouraging results.
- Similarly, a short ex-vivo treatment of vein grafts with genes that
should prevent uncontrolled growth of the vein wall used for bypass
grafts, was shown to be substantially bebeficial to many patients
treated by Dr. Dzau (Brigham and Women's Hospital, Boston MA). The
treatment strongly reduced the cases of bypass occlusion (restenosis)
over mid- and long term. Furthermore, extremely promisising
effects are declared by ONYX, a company that uses adenoviral vectors
that preferentially proliferate in tumor cells. According to press
releases, there trials are now in phaseIII, which means close to
marketing. Other successes are reported in large animal models, such
as in models of Hemophilia. Therefore, we can expect that many gene
therapy protocols will enter Phase II trial within one or two years
and some of them Phase III within three to five years. This means
that before 2005 the first clinical aplications will be probably
available in the clinics. Certainly, for some diseases we will have
to wait still many years before finding a convincing gene-based
protocol. However, as any other technology, gene therapy must be
given the right to enter adolescence and to mature into a fully
functional body.
Please contact us if you wish to know more about the progress, successes and insuccesses of clinical trials.
Is gene therapy necessary?
text in preparation
Please contact us if you wish to know or discuss more about the presumed or effective necessity of gene therapy
WHAT IS THE NFP37?
What is an NFP?
- an NFP is a 'National-Forschungs-Programm' (national research
program). It is a publically funded research coordination organ in
which an area of particular current social interest is investigated.
The idea is that the NFP will allocate extra funds to this research
area for a limited time (NFP last 5 years), thereby allowing good
research teams to emerge, become credible and continue on their own
by attracting subsequent financing. A 'good' NFP should therefore not
end by December 31 of the termination year, but leave a trace behind
that fosters further networking within the research area.
NFP themes can be proposed by any credible goup of scientists, and
they can be dedicated to the most disparate themes (from trans-alpine
traffic to immigratzion politics, to alternative medicine).
Ultimately, it is the central government who decides which program
proposal to sustain with the funding (usually between 10 and 15 Mio
Sfr for 5 years). Once decided, the management is then taken over by
the division IV of the Nationalfonds, that will assign a
chronological number to the program, name a president, a director and
a board of experts. This team will call for or invite project
proposals and then the program starts its operational years. At the
end, one expects a final report which summarizes the achieved goals
and the perspectives.
The NFP37
Th NFP37 'somatic gene therapy' was proposed in 1993-94 by three
distinguished Swiss scientists: Charles Weissmann (Zürich),
Bernard Mach (Genève), Marco Baggiolini (Bern). It was
accepted and received the serial number 37, which has no further
particular significance. In 1995 there was a call for project
proposals and 21 thereof were considered after extensive peer review.
In 1996 The director S. Rusconi was nominated and the operative part
was started. Most projects were granted for a period of 36 months,
and therefore subjected to reassessment in 1998. In the same year, a
call for projects for the second phase was advertised. 9 initial
projects were discontinued , 2 were intermediately running, and 10
new ones were added. The peer review of this second phase involved 78
distinguished scientists from all countries.
Besides funding research in form of salaries and consumables (for a
total of 14 Mio Sfr) The NFP37 has organised already three annual
meetings, contributed to the organisation of three topical symposia
and to a technology assessment project ('Somatische Gentherapie')
runned by the Swiss research council. During the first phase
(1996-1999), several scientific publications and three patents have
been filed by the research teams sponsored by the NFP37.
Please click te corresponding menus if you want to get detailed nformations about the scientific activities in:
Please contact us if you wish to know more about the history and dreams of the NFP37 'somatic gene therapy'.
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