Senthil Bhoopalan Lab

The overarching objective within the Bhoopalan Lab is to advance our understanding of the mechanisms underlying hematopoietic failure in inherited bone marrow failure disorders. Among such inherited disorders is DBA, which is usually caused by heterozygous loss-of-function mutations in one of 24 ribosomal protein genes, with RPS19 mutations accounting for 25% of cases. A lack of patient bone marrow cells is a significant limitation in studying these rare disorders. We use genome editing tools, such as CRISPR and base editing, to model these mutations in CD34+ hematopoietic stem/progenitor cells and utilize cutting-edge techniques, such as single-cell RNA-Seq, single-cell whole genome sequencing, CUT&RUN and multi-omics to understand mechanisms driving hematopoietic failure in these catastrophic diseases of childhood. 

Using these insights, we strive to develop novel therapies for patients with these disorders. Our group has developed a lentiviral vector encoding RPS19, which we are currently advancing toward clinical use for certain eligible patients with DBA. However, there are several other rarer forms of DBA and other rarer bone marrow failure disorders that are dosage-sensitive or cell type-specific, which precludes the use of lentiviral vector gene therapy; these mutations require a more targeted approach. Through the St. Jude blue-sky initiative, PARADIGM, we are developing approaches that use base editors and prime editors to address these unique mutations in patients.