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Development of novel therapies for Diamond-Blackfan Anemia

Debnath, Shubhranshu LU (2017)
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD Liu, Johnson M, The Feinstein Institute for Medical Research
organization
publishing date
type
Thesis
publication status
published
pages
78 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund
defense date
2017-09-06 09:00
ISBN
978-91-7619-489-8
language
English
LU publication?
yes
id
875a91b2-ce0c-4bfe-96af-b8e43c130013
date added to LUP
2017-08-16 16:15:36
date last changed
2017-08-18 13:24:24
@phdthesis{875a91b2-ce0c-4bfe-96af-b8e43c130013,
  abstract     = {Diamond-Blackfan anemia is a congenital erythroid hypoplasia manifesting early in<br/>life. In at least 60-70% of cases, DBA is caused by a functional haploinsufficiency<br/>of genes encoding for ribosomal proteins. Approximately, 25% percent of patients<br/>have mutations in the gene encoding ribosomal protein S19 (RPS19). The<br/>hematological profile of DBA patients shows macrocytic anemia with<br/>reticulocytopenia, normal or decreased levels of neutrophils and variable platelets<br/>counts. DBA patients also exhibit various non-hematological manifestations such<br/>as physical abnormalities and cancer predisposition. Corticosteroids are the main<br/>therapeutic option in DBA. Around 80% of the patients initially respond to<br/>corticosteroids, but only 40% of patients sustain the therapeutic response and the<br/>remaining 40% of patients need chronic blood transfusion. Twenty% of patients go<br/>into spontaneous remission and maintain an acceptable hemoglobin level without<br/>therapeutic intervention. The only curative treatment available for DBA patients is<br/>allogeneic bone marrow transplantation.<br/>This thesis focuses on understanding the disease pathogenesis and development of<br/>novel therapies for DBA. In Article-I we sought to understand the physiological<br/>relevance of the 5S RNP-Mdm2-p53 pathway for generation of the erythroid defect<br/>upon RPS19 deficiency. In Article-II we aimed to evaluate the therapeutic effect of<br/>the amino acid L-leucine in the treatment of DBA. In Article-III and IV we examine<br/>the feasibility of RPS19 gene therapy in the treatment of RPS19 deficient Diamond<br/>Blackfan Anemia.<br/>In summary, this work focuses on basic and translational research towards<br/>evaluating novel therapies and understanding molecular mechanisms for DBA.},
  author       = {Debnath, Shubhranshu},
  isbn         = {978-91-7619-489-8},
  language     = {eng},
  pages        = {78},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Development of novel therapies for Diamond-Blackfan Anemia},
  year         = {2017},
}