Rula Zain

The signaling cascade that triggers the B cell mediated immune-response upon antigen binding to the B cell receptor is critically dependent on Bruton’s tyrosine kinase (BTK). The BCR signaling pathway remains critical for survival and proliferation of transformed B cells. The introduction of BTK inhibitors (BTKi) to interfere with this signaling pathway has revolutionized treatment of chronic lymphocytic leukemia (CLL). In CLL, BTKi treatment cause tumor cells to exit tissues and enter peripheral blood where they over time waste away.Long-term BTKi treatment is burdened by side effects and the development of treatment resistant CLL. Curiously, the cessation of BTKi treatment is not associated with disease progression. Instead, many patients remain in long-term sustained remission. This suggests that BTKi can induce changes to CLL cells or tumor microenvironment (TME) that persist long-term.The proposed project aims to:1. Perform temporal analysis of plasma biomarkers and CLL cells during treatment with 2nd generation BTKi.2. Disentangle direct and TME mediated effects of BTKi treatment on CLL using a combined BTKi resistance (BTK C481S) and CLL mouse model.3. Identify CLL-intrinsic and TME mediated factors contributing to long-term sustained remission after the withdrawal of BTKi treatment.Our hope is that this will lead to improved understanding of how BTK inhibitors work and how they can be used to provide each individual patient with the best possible treatment.

The research project focuses on precision medicine

therapeutic oligonucleotides (ONs). Our unique niche is to develop anti-gene ONs (A-GOs), which bind to the DNA duplex, where our strategy is world-leading. We found that A-GOs binding to the disease gene in tandem repeat-expansion disorders (TREDs), such as Huntington’s disease (HD) and Friedreich’s ataxia (FRDA), significantly modulates gene expression. The fact that A-GOs binding within the chromatin down-regulates the expression of Huntingtin in patient cells, is by all criteria a breakthrough. Also, our recent findings demonstrate that specifically designed A-GOs not only revert the gene silencing in FRDA but also block the repeat expansion in mammalian cells. In other words, for the first time we can target the root cause of these diseases, the repeat expansion itself. Moreover, our accumulated expertise in nucleic acid therapeutics for genetic diseases has an evident added-value to the development of additional gene-therapies, such as gene editing.  We aim to move our precision medicine ONs closer to the clinics focusing on the following:Advance our A-GOs therapeutic concept for FRDA and HD by studying their effect in patient-derived cells, differentiated iPS cells, and in animal models with focus on disease prevention and treatment.Develop FRDA gene therapy based on an in-house minicircle technology.Study the mechanisms underlying repeat expansions in FRDA and HD and in the novel TRED named CANVAS.