Home Open letters “Open letter” to all those fighting against thalassaemia


The Thalassaemia International Federation (TIF), with its biennial Conferences, plays a unique and irreplaceable role: it periodically assembles numerous scientists, unfortunately not all of them, to inform us of the ‘state of the art’ in all the sectors involved in thalassaemia research.
The Conference in Palermo on 15-19 October 2003 is part of this project and we are truly grateful to the President Panos Englezos, his staff and everyone who has contributed to organizing this ‘event’ for the opportunity they have offered us to learn about the latest research achievements.
Thalassaemia sufferers, who daily have to face up to the discomforts of a very stressful chronic illness, are of course interested in finding out about any innovations in research which have already reached the clinical phase. We agree with them and we appreciate the irreplaceable work carried out by doctors all over the world. Only their daily efforts can help sufferers to better come to terms with their illness.
When we have had the opportunity, our Association has financed (and will continue to do so in the future) clinical research projects that enable current therapies to be improved. However, thalassaemia sufferers throughout the world nurture a secret hope: that research can not only improve treatment but find a radical replacement for it and that gene research can be developed in order to reach a decisive solution to the problem.
The Associazione Veneta per la Lotta alla Talassemia of Rovigo, a small association of sufferers and their parents (around 130 members), operating in the Veneto, a region of Northern Italy, has also undertaken a new ‘enterprise’.

To avoid boring the readers, we’ll leave aside the account of the previous years (which can be found in other sections of this feature) and go straight to 2000.
In July of that year an Agreement was signed (all the documents mentioned can be found on the website www.talassemiaricerca.unife.it, now also in English) between Prof. Roberto Gambari, Director of the Biotechnology Centre at Ferrara University, and the President of the Associazione Veneta.
This is truly an exceptional event: a voluntary Association in active discussion with a University and directly involved in choices that may influence the quality of life of many ill people throughout the world.
The Biotechnology Centre supplies all its exceptional technological equipment and research staff, while the AVLT, with a funding of 258,228 Euro (the fruit of exhausting annual fund-raising campaigns), guarantees the availability of new researchers, the purchase of small items of equipment, applying for patents, etc. for the first four years of activity.
That Agreement did not appear out of thin air; it is the conclusion of a collaboration that had begun in 1996 and had already led to some major decisions:
- in October 1998 the first patent was registered;
- in the same month Prof. Stefano Rivella, on behalf of Prof. Michel Sadelain’s research Group in New York, held a seminar in Ferrara on the subject of gene therapy;
- in February 1999 the first meeting was held with Chiesi Farmaceutici based in Parma;
- in January 2000, Prof. Eitan Fibach from JerusalemUniversity held a seminar in Ferrara on the application of the ‘method’ that is named after him;
- in March 2000 a second patent was registered.

These events outline, in nuce, a project whose aim was to:
1) safeguard the results of Prof. Gambari and his Group’s research by patenting them;
2) put together the pure research, aimed at identifying and characterizing HbF inducing molecules, with expert researchers on these molecules both in vitro and ex vivo and the pharmaceutical industry with a view to developing new drugs;
3) set up relations of collaboration with forward-thinking researchers in the field of gene therapy in thalassaemia.
This project is clearly set out in the July 2000 Agreement which led to the birth of the “Laboratory for the Development of Pharmacological and Pharmacogenomic Therapy of Thalassaemia” (Thal-Lab).
Three years after that event, the “Laboratory” has consolidated its operational line and the Ferrara-Jerusalem-New York triangle has become the symbol for a no-holds-barred battle to defeat the illness.
Prof. Gambari’s research team in Ferrara has considerably increased its activity, leading to the registration of further PCT international patents. The Thal-Lab now holds the following patents:
- patent no. PCT/EP01/02804 dated 13 March 2001: “Synthetic oligonucleotides as inducers of erythroid differentiation”;
- patent no. PCT/IB02/02628 dated 1 July 2002: "Use of heterocyclic and benzoheterocyclic polyamides structurally related to the natural antibiotic distamycin A for the treatment of beta-thalassemia";
- patent no. PCT/IB02/04042 dated 26 September 2002: “3-deoxy-3-amide derivatives of carbohydrates as inducers of erythroid cell differentiation”;
- patent no. PCT/IB03/02632 dated 3 July 2003: “A novel use of rapamycin and structural analogues thereof”;
- patent no. PCT/IB03/03462 dated 30 July 2003: “A novel use of angelicina and structural analogues thereof”.
As can be seen, the inducers of foetal haemoglobin studied are many and yet more are being sought because, as experience has shown, it is to be expected that thalassaemics will not all respond in the same way to the same substance and many substances are therefore needed in order to achieve the best results in all the patients treated.
The Thal-Lab does not have a patent for use on another substance, mithramycin, since in 1999 it was the subject of an article in a scientific journal, the British Journal of Haematology, which has prevented the patent from being registered. It is nevertheless a substance that is extremely effective in inducing foetal haemoglobin, as was evidenced in the article “Mithramycin induces fetal haemoglobin production in normal and thalassemic human erythroid precursor cells”, published last August in Blood, the most important scientific journal on experimental haematology.
As for collaboration with the pharmaceutical industry, it is now well-established with Chiesi Farmaceutici di Parma, while talks are underway with Pfizer and Wyeth.
The research front is led in Jerusalem by Prof. Eitan Fibach, obviously the most expert user of the ‘method’ named after him, which tests the efficacy of the substances from the Thal-Lab in vitro and ex vivo, on cells of both healthy and thalassaemic subjects.
The third research phase, experimenting on animals, takes place in New York. The Thal-Lab has set-up a collaboration with Prof. Stefano Rivella, the Director of a Gene Research Laboratory at the Weill Medical College of Cornell University. Prof. Rivella’s animal breeding department has made it possible to begin testing mithramycin on healthy mice and mice with intermediate thalassaemia and will move on to transgenic mice, which will soon be available. The same procedure will be followed for the other experimental substances ex vivo in Jerusalem.
The collaboration with Prof. Rivella is not limited just to testing ‘the Ferrara substances’, but also involves supporting research into gene therapies for thalassaemia, which Prof. Rivella is pioneering, as evidenced by the article, published in Blood last April, “A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer”. As Prof. Rivella himself explained, in an interview with “EX” published in the same month of April, “In all the animals suffering from beta thalassaemia major, the vector made it possible, without transfusions, to achieve haemoglobin levels from zero to 5-12 g/dL…Our final goal is to discover how to ‘always’ reach haemoglobin values of 12 g/dL or even higher”.
It is clear that both Prof. Gambari’s Thal-Lab in Ferrara, on the pharmacological therapy research front, and Prof. Rivella’s Genetic Laboratory in New York, on the gene research front, have provided some of the most noteworthy results achieved so far in those fields. It is therefore in the interests of all thalassaemics and their families that these activities are accelerated.
Within this overall picture, what role has the Associazione Veneta played? First of all, it promoted the meeting between Professors Gambari, Rivella and Fibach and endorsed agreements that laid solid foundations for their collaboration. With the sum of money put at Thal-Lab’s disposal, boosted by considerable contributions from the Fondazione Cassa di Risparmio di Padova e Rovigo, the AVLT, also making use of co-financing, has been able to be present over a vast operative area. That presence is substantiated today as follows:
- a full grant to one of Prof. Gambari’s collaborators in Ferrara;
- a full grant to one of Prof. Fibach’s collaborators in Jerusalem;
- a grant shared fifty-fifty with Ferrara University for one of Prof. Gambari’s collaborators who has gone to work in Prof. Rivella’s Laboratory in New York;
- a grant co-financed with Zurich University for one of Prof. Gambari’s collaborators who has gone to work with Prof. Pier Luigi Luisi in that Swiss city;
- a grant co-financed with Ferrara University for one of Prof. Gambari’s collaborators who is working in the University’s Department of Chemistry and Molecular Biology;
- a grant shared fifty-fifty with the Ferrara Associazione per la lotta alla talassemia (Association for the Fight against Thalassaemia) for one of the collaborators of Prof. Giorgio Catelani at Pisa University, himself a precious collaborator of the Thal-Lab.
Modesty aside, we feel we have greatly contributed to setting up and developing a research centre that has no equal in the world (at least as far as we are aware). If there are other similar, or even more advanced, realities that have been able to mobilize pure research, the protection of the results of that research by taking out patents, well-established collaboration with the pharmaceutical industry (without which there is no hope of obtaining the development of new drugs) and experiments on animals, it would be most useful if everyone could be made aware of their activities and such centres could be ‘twinned’ with a view to a co-ordinated worldwide development of everything that is being done to defeat thalassaemia.
There’s room for all the Thalassaemia Associations in this fight! We do not claim exclusive rights – on the contrary, we hope that many other Associations from all over the world will add their contribution in the fight against an illness whose days might be numbered.
We also expect a response to the problems of the research we’ve described from the Governments of all the countries where thalassaemia is a serious socio-medical issue.
If the costs are shared out among many, the burden to each becomes modest. It is important first of all to award research grants and enable the purchase of the materials needed for the research.
How can the research be financed? You should contact the groups mentioned above, whose addresses are provided separately. You should contact them to express your interest and to gather all the information needed to make a financial commitment.
The Board of Thal-Lab recently approved a five-year Plan for 2004-2008 to develop its activities entitled “New frontiers of thalasaemia research”, breaking it down into numerous specific projects in turn divided into sub-projects with the associated costs.
Anyone who would like to help the Thal-Lab can choose to finance a single project or sub-project, and ask to receive regular reports on its progress.
Prof. Rivella has also drawn up a five-year Plan of activity at his Laboratory, again for 2004-2008, entitled “The development of new instruments in the field of gene and pharmacological therapy to treat thalassaemia”. It too is subdivided into projects and subprojects and can be financed according to objectives whose timelines are fixed throughout the Plan. The same applies here as for the Thal-Lab: Anyone who would like to help the Laboratory directed by Prof. Rivella can choose to finance a single project or sub-project, and ask to receive regular reports on its progress.
No-one can fall back on an alibi anymore. We can’t expect to see radical changes in thalassaemia therapy by just sitting back and waiting!
We also want to launch an appeal to all the researchers who, throughout the world, are proceeding with research, perhaps alone. Equally we would like our voice to be heard by all the doctors who daily treat thousands of ill people all over the world in their surgeries.
We are not asking anyone to give up their autonomy. We are simply asking you to be aware of the existence of this new organization dedicated to research called Thal-Lab, located at FerraraUniversity in Italy, and the Thalassaemia Gene Therapy Research Laboratory, at CornellUniversity in New York. We are asking you to set up collaborations, perhaps in new forms to be invented and agreed on, because co-ordinated multi-centre work can bring about more rapid and effective results.
We are suggesting not a research ‘hierarchy’ but rather the creation of a widespread network exchanging information, the drawing up of a programme of scheduled meetings and even, why not?, the promotion of creative friendships.
Our last, but not least important, appeal we would like to make to the TIF. With its well-established international connections, it could extend an invitation to all the pertinent Associations and all the relevant National and World Health organizations to support, in any way possible, research such as the work taking place in the Ferrara and New York Laboratories. The TIF could, alongside their primary objectives pursued so far of prevention and clinical treatment, also place support for the research we have described at length. The TIF also possesses an instrument, its three-monthly Magazine, which could also become an information vehicle for this research. And its important commitment in this new sector could begin with a meeting, at a time and place to be agreed, between its President Panos Englezos and its Scientific Co-ordinator Prof. Androulla Aleftheriou and the Directors Gambari and Rivella.
In conclusion, we want to point out that we do not wish to create illusions. On the contrary, we want to base the hopes of all thalassaemia sufferers on concrete facts, on research centres that work and are willing to provide any information requested.
There are no easy, short-term solutions. The timescale of research is different from that of the expectations of the ill. But the hope will remain vain if it is not sustained by the efforts of everyone involved so that it can one day become a reality.

Elio Zago, President AVLT

(translation by Ms Mary Hawkes)

(“EX”, year XXIX, n. 6, September 2003)


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