Request and background information
In April 2010, a father whose children have galactosemia suggested that Cinderella develop a drug for this disorder. Galactosemia is an autosomal (not sex linked) recessive hereditary disorder with stepchild status. In Western Europe it occurs in one in 30,000 births. It is a metabolic disorder that affects the enzymatic breakdown of galactose, a sugar formed during the digestion of lactose. The only available treatment is to avoid dairy products by means of a strict diet implemented as soon after birth as possible. Such a diet allows patients to develop fairly normally, although there can be long-term complications such as speech difficulties, low IQ, coordination problems, cataracts and reduced fertility in women. Galactosemia is caused by mutations in one of three different enzymes and the different forms of the disease differ in severity. The question arose why it was not possible to treat galactosemia with enzyme restitution and whether Cinderella could help in the development of such treatment.
What Cinderella has done
We looked at current medical interventions with regard to galactosemia in the Netherlands and had several discussions with experts at the academic medical centers in Amsterdam (AMC), Maastricht and Nijmegen. They all agreed that while galactose restriction has been the only accepted treatment option for decades, it is still not known whether such restriction actually influences disease progression. It is certainly safe to say that more effective treatment is needed.
At that time there were two treatment options: enzyme restitution and inhibition of the enzyme galactokinase. The first option appeared to be feasible by using recombinant DNA technology to produce the enzyme. However, before applying it in the clinic it would first be necessary to establish whether the treatment is effective in experimental animals. Unfortunately we knew of no suitable animal model for this disease and therefore such a model would first need to be developed.
In August 2010, Cinderella informed the experts that it was likely that university researchers would be prepared to work on this project because there was a good chance of scientifically interesting results. One of the criteria for Cinderella’s adoption of a stepchild is that preclinical studies have already shown it to be promising. Although galactosidase restitution did not meet this criterion, in this case Cinderella was prepared to relax its policy if the following requirements could be met:
1. Clinical researchers must participate in the project and such researchers must be prepared to administer the enzyme to their patients in a clinical trial as soon as it becomes available, assuming positive results are obtained in preclinical studies.
2. From the beginning, the project must be supported – morally at least – by patients’ groups in the USA and in Europe.
3. During development of the new treatment, all participants must endorse Cinderella’s principles, in particular: no pursuit of profit, no unnecessary costs, shortest route from “bench to bedside”.
Cinderella proposed that the major players (Bosch and Wijburg (Amsterdam), Rubio and Geraedts (Maastricht), Berry (Harvard), Elsas (Miami)) should come together, form a consortium and draw up a plan of action.
As a result of the overwhelming interest following Cinderella’s PR campaign in the latter part of 2010, the subsequent numerous applications for new stepchildren, and because no pressure was being applied by patients or doctors, nothing was done about this proposal for a year. In September 2011, Cinderella was approached by the Tjallingh Roorda foundation, which was interested in providing financial support for the galactosemia project. This provided new stimulus to go ahead with the abovementioned proposal.
Our Dutch contacts indicated a preference for a more extensive discussion of the plan in a smaller setting, and on 7 March 2012 a meeting was held between Dr. A.M. Bosch, Prof. R.J. Wanders, Prof. F.A. Wijburg and Prof. C.E. Hollak (AMC); Dr. E. Rubio and Prof. J. Geraedts (UMC Maastricht); and H. Verweij and D.W. van Bekkum (Cinderella). Although this meeting did generate an idea for a third treatment option, namely gene therapy, the participants all agreed that there was still insufficient knowledge about galactosemia to justify enzyme production for clinical use. Cinderella will inform the proposer of this collective viewpoint and publish it on her website.
Dr. Bosch and Dr. Rubio are currently establishing a joint center of expertise for galactosemia in the Netherlands. An international consortium for research into galactosemia is also being set up. For more information on the consortium, please contact Estela Rubio <firstname.lastname@example.org> phone: +31(0)43 3872920.
Based on the positive experiences with enzyme therapy in other metabolic disorders, we initially assumed that this would also be an appropriate and feasible option to improve the treatment of galactosemia. This was not clearly refuted during our first meetings with experts. Further examination of the details revealed that since we had insufficient knowledge of the underlying disease mechanism, we could not select a reliable preclinical disease model. We therefore conclude that the development of this treatment method is not yet sufficiently advanced to meet Cinderella’s criterion of “promising”.
It is gratifying that in the meantime galactosemia specialized physicians and researchers and patient organizations work together to address these problems.
– AM Bosch. Classical galactosaemia revisited. J Inherit Metab Dis (2006)29: 516-525
– Berry GT and JL Elzas. Introduction to the Maastricht workshop: lessons from the past and new directions in galactosemia. J Inherit Metab Dis (2011)34:249-255
– E. Rubio et al. Letter of intent. March 19, 2012 A European-American network for galactosemia