Development of novel therapies for Diamond-Blackfan Anemia

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Diamond-Blackfan anemia is a congenital erythroid hypoplasia manifesting early in
life. In at least 60-70% of cases, DBA is caused by a functional haploinsufficiency
of genes encoding for ribosomal proteins. Approximately, 25% percent of patients
have mutations in the gene encoding ribosomal protein S19 (RPS19). The
hematological profile of DBA patients shows macrocytic anemia with
reticulocytopenia, normal or decreased levels of neutrophils and variable platelets
counts. DBA patients also exhibit various non-hematological manifestations such
as physical abnormalities and cancer predisposition. Corticosteroids are the main
therapeutic option in DBA. Around 80% of the patients initially respond to
corticosteroids, but only 40% of patients sustain the therapeutic response and the
remaining 40% of patients need chronic blood transfusion. Twenty% of patients go
into spontaneous remission and maintain an acceptable hemoglobin level without
therapeutic intervention. The only curative treatment available for DBA patients is
allogeneic bone marrow transplantation.
This thesis focuses on understanding the disease pathogenesis and development of
novel therapies for DBA. In Article-I we sought to understand the physiological
relevance of the 5S RNP-Mdm2-p53 pathway for generation of the erythroid defect
upon RPS19 deficiency. In Article-II we aimed to evaluate the therapeutic effect of
the amino acid L-leucine in the treatment of DBA. In Article-III and IV we examine
the feasibility of RPS19 gene therapy in the treatment of RPS19 deficient Diamond
Blackfan Anemia.
In summary, this work focuses on basic and translational research towards
evaluating novel therapies and understanding molecular mechanisms for DBA.

Details

Authors
  • Shubhranshu Debnath
Organisations
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2017 Sep 6
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-489-8
Publication statusPublished - 2017
Publication categoryResearch

Bibliographic note

Defence details Date: 2017-09-06 Time: 09:00 Place: Segerfalksalen, BMC A10, Sölvegatan 17, Lund External reviewer(s) Name: Liu, Johnson M Title: MD Affiliation: The Feinstein Institute for Medical Research --- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:107

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Debnath, S., Jaako, P., Siva, K., Rothe, M., Chen, J., Maria Dahl, Gaspar, H. B., Johan Flygare, Schambach, A. & Stefan Karlsson, 2017, In : Molecular Therapy. 25, 8, p. 1805-1814

Research output: Contribution to journalArticle

Jaako, P., Debnath, S., Karin Olsson, Zhang, Y., Johan Flygare, Lindström, M. S., David Bryder & Stefan Karlsson, 2015, In : Leukemia. 29, 11, p. 2221-2229

Research output: Contribution to journalArticle

Jaako, P., Debnath, S., Karin Olsson, Modlich, U., Rothe, M., Schambach, A., Johan Flygare & Stefan Karlsson, 2014, In : Haematologica. 99, 12, p. 1792-1798

Research output: Contribution to journalArticle

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