T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although outcome has improved throughout the years with the use of combined chemotherapy, the aggressive regimens required for treatment efficacy often lead to significant short- and long-term side effects. Moreover, a significant fraction of T-ALL patients relapse, which have extremely poor prognosis.
The current project aligns with the core goal of our ERC Consolidator Grant IL7sigNETure (CoG-648455) to generate new targeted therapies for improved treatment of T-ALL.
We have envisioned a novel and ambitious gene therapy system that takes advantage of tumor specific microRNA (miR) expression profiles to selectively deliver a killing gene to tumor cells. MiRs are ~22 nucleotides small non-coding RNAs that regulate gene expression post-transcriptionally. Importantly, miR expression profiles have been shown to distinguish tumor from normal cells and tumors of different developmental origins and differentiation stages. Thus, we propose to develop a gene therapy that explores the differences between T-ALL and normal cells regarding their miR expression pattern, in order to: specifically identify leukemia cells and selectively induce the expression of a killing gene in the malignant cells. This microRNA-regulated cell death-inducing system has the transformative potential to overcome efficacy and side-effect limitations associated with current therapeutic strategies in T-ALL.
Overall, the scientific breakthrough of this project is the development of a gene therapy cell death-inducing system (miRTo) that uses cell-endogenous miRs to regulate the expression of a killing gene specifically in target cells. In addition to the stringent regulation by miRs specifically present and absent in target cells, the expression of the killing gene is further regulated by an inhibitor delivered simultaneously by the same gene therapy system and also regulated by cell-endogenous miRs. This dual layer of regulation, in one single vector, has not been applied before and will increase the specificity of this system.
Importantly, the way the technology is designed allows simple modifications to be introduced. The flexibility and adaptability of our technology makes it ideal for precision medicine, giving us the potential to generate personalized therapies and to treat a broad spectrum of diseases, in which patients attained of severe medical conditions and left without treatment alternatives may clinically benefit from the targeted delivery of a therapeutic gene. As such, the prospective clinical applications of this gene therapy are numerous, including, but not limited to, cancer and, in particular T-ALL, our main therapeutic focus.
