Pathogenic and therapeutic mechanisms of novel therapies for bone marrow failure in Diamond-Blackfan Anemia

Diamond-Blackfan Anemia (DBA) is a congenital form of severe anemia with no safe and effective therapy, leaving patients with short life expectancy.

While it is known DBA is caused by inherited mutations in ribosomal protein genes, the mechanism causing depletion of erythroid precursor cells is highly debated.

The overall goals of this proposal are to identify cell-specific disease mechanisms in DBA and to develop new therapies.

Both aims in the project are based on implementation of CITE-Seq, a single cell sequencing method that captures a snapshot the cell surface proteins as well as the transcriptome of single cells. Aim 1.

My first aim is to dissect the molecular and cellular therapeutic mechanisms of two promising DBA drug candidates identified in my lab. Aim 2.

The second aim is to map out critically failing cell types in DBA and the underlying cell-type-specific pathogenic mechanisms.

CITE-Seq of corrected vs. uncorrected cells in patients undergoing gene therapy will be the ultimate experimental setting for elucidating cell-specific disease mechanisms in DBA.

Significance.Completion of the study will provide a comprehensive pathophysiological characterization of this enigmatic disease and a leap forward towards better treatment options for the patients.