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A search for novel drugs to treat the haemoglobinopathies.


The treatment of sickle cell anaemia and ß thalassaemia is at present inadequate, expensive and unsatisfactory. There is an urgent need for novel treatments and two possibilities can be envisioned. Firstly the treatment with small molecules that interfere with the transcription process and may reactivate the y-globin genes which are normally suppressed in adults. This approach is the subject of this proposal. The second possibility would be gene therapy, which is the subject of another proposal. Here we propose to make mouse models which can be used to screen and test compounds that interfere with y globin gene suppression and to study factors that are important in the switching from y to ß globin genes. The identification of such factors may provide a rational approach to design molecules that interfere with y and ß globin gene expression.
The objectives are:
1. The generation of transgenic mice which model human thalassaemia and sickle cell anaemia.
2. The generation of transgenic mice which carry a complete human ß-globin gene domain in which one of the foetal globin genes expresses luciferase. 3. The generation of erythroid cell lines from the luciferase mice (2 above) by infection with Friend virus or crossing with transgenic mice that carry a GATA-T antigen construct (Ottolenghi). These cell lines will be used in a robotic screen for novel therapeutic compounds that can activate y globin gene expression in the adult.
4. The testing of candidate therapeutic compounds in transgenic mice and human erythroid cell cultures.
5. The identification of transcription elements and their cognate transcription factors important for y globin gene activation/suppression and the switch to ß globin expression.
Keywords: Haemoglobinopathies, drug discovery, transcriptional regulation, transgenic mouse models.


Erasmus Universiteit Rotterdam
50,Dr. Molewaterplein
3000 DR Rotterdam

Participants (5)

Foundation for Research and Technology-Hellas

71110 Heraklion
National and Kapodestrian University of Athens
17,Aghiou Thoma Street
11527 Athens
Piazza Della Scienza 2
20126 Milano
United Medical and Dental Schools of Guy's and St Thomas's Hospitals
United Kingdom
London Bridge
SE1 9RT London
Universita degli Studi di Cagliari
Via Jenner S/n
09100 Cagliari