«What is 'gene therapy'

«What is the 'NFP37'

c'est quoi?
Was ist?
What is?


(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:



a segment of DNA that specifies a function (example: gene for insulin). The information of genes is first temporary transcribed in RNA then translated in proteins (see below).


a molecule composed of a string of aminoacids (building blocks of proteins). The folding specifies a structural or a functional elements. In a cell there are at least 5000 types of proteins where each type is present in large numbers (from 10'000 to 1'000'000 molecules).


in the modern conception: a procedure by which genetically modified micro-organisms or cell cultures are used to produce a relevant compound (an antibody, a vaccine, a growth factor, a hormone an enzyme, ...)


proteins that are produced by biotechnological procedures. They are usually applied by injection. Examples: interferon (to treat cancers, infections, degenerations), alpha-antitrypsin (to treat heart attacks), growth hormone (to treat various conditions), insulin (to treat diabetes), erythropoietin (to treat anemias) etc...


desoxyribonucleic acid, the carrier of genetic information in form of sequence of bases (or nucleotides)


The fundamental building blocks of DNA: A, G, C, T their sequence specifies the genetic language


example: vaccination. By exposing the organism to new proteins (viral or bacterial antigens) one raises its immune system. Today, an increasing number of vaccinations is prospected to be feasible by direct gene transfer.


a way of relieveing the symptoms of a disease without curing the disease itself. Examples: reduction of pain, rehabilitation of movement, slowing down of progressive degeneration, acceleration of natural or conventional healing process


a way of eradicating the cause of the disease and re-establishing thereby the normal function. Example: antibiotic-mediated eradication of infections.

gene transfer

the procedure by which purified genes are transported into cells or tissues. The transfer requires a vector that can deposit the gene into the cell nucleus, wherefrom it can be expressed.

efficiency of gene transfer

the efficiency of gene transfer varies depending on the vector used and the target system. When transfecting cell cultures (monolayers cultured in petri dishes) with chemically based vehicles (liposomes, polycations, calcium phosphate coprecipitate etc) one obtains anything between 0.1 and 10 % of translently transformed cells. When transferring genes in tissues, these values decrease by at least 100-fold. Viral vehicles allow transfer efficiencies from 10 to 100%, both in cell cultures and in tissues.


a vehicle by which genes can be carried inside cells: there are physical vectors (microinjection, pressure, electroporation, micro-projectile bombardments); chemical vectors (liposomes, cationic carriers, insoluble salt particles); biochemical vectors: complexing with proteins that are engulfed via surfece receptors; biological vectors: packaging into viral particles.

viral vectors

engineered viruses whose genetic layout has been modified to include therapeutic or marker genes. In this process the viruses are mostly made unable to replicate outside of laboratory conditions. Examples:; recombinant adeno vectors, recombinant HIV vectors. These recombinant viruses must be grown inside specially engineered cells, the so-called packaging cells, and are unable to replicate in other cells.


an infectious particle which is 1000-10'000 smaller than a cell. It carries the necessary components to enter into the cell and to express its genetic program, thereby generating new viral particles that will infect further cells etc. Example: influenza virus, Herpes virus, AIDS virus

non-viral vectors

Chemical formulations of particles containing DNA and that are capable of entering cells by various ways (endocytosis or other transports). As of today, non viral vectors are at least 1000-fold less efficient than viral vehicles.

clinical trials

A form of experimentation in which human beings are involved. They are preceded by pre-clinical experiments in which the toxicity of the compounds is tested on animals. The initiation of clinical trials is submitted to strict rules for ethical and safety questions. The clinical trials are conducted in three phases: Phase I (few patients, test only side effects); Phase II (up to nx100 patients, testing eficacy with escalating doses); Phase III (up to several 1000 patients, testing efficacy in comparison with a negative control).

GT in Switzerland

some recent data are presented in the review article Molecular Medicine by S Rusconi, 1999.

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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.

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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.

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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.

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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.


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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 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.

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Please contact us if you wish to know more about the history and dreams of the NFP37 'somatic gene therapy'.

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