Project Term
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Project Summary
Mutations affecting RNA splicing factors are the most common class of mutations in patients with myelodysplastic syndromes and related myeloid neoplasms. Although these mutations cause a gain of function, there are no treatments which selectively inhibit the enzymatic activity of the mutant spliceosome. To address this issue, here we have developed a new precision therapeutic that selectively target and eliminate cells carrying cancer-causing mutations affecting the RNA splicing factor U2AF1.
Lay Abstract
One of the most unexpected findings from genetic studies of patients with myelodysplastic syndromes (MDS) was the discovery of frequent mutations in the RNA splicing machinery in MDS cells. Our genetic code is specified by DNA molecules, which are transcribed into precursor messenger RNA (pre-mRNA). This pre-mRNA, in turn, undergoes the process of RNA splicing to be converted into mature RNA which finally encodes the proteins that serve as the building blocks of our cells.
Our group and others have discovered that the mutations in the RNA splicing machinery seen in MDS confer an alteration of function. We have now created a technology where we engineer pre-mRNA that when introduced into cells, cells with MDS-associated splicing machinery splice this engineered RNA to produce a protein that ultimately eliminates MDS. We term this approach “synthetic introns.”
This proposal is aimed at developing this approach for mutations in the RNA splicing factor U2AF1. U2AF1 mutations are common in patients with MDS and acute myeloid leukemia (AML) and associated with poor outcome. We have already generated early versions of synthetic introns which respond to U2AF1 mutations and demonstrate early evidence of activity in laboratory cell line models and in mice harboring U2AF1 mutant AML.
Our proposal will optimize these synthetic introns and come up with improved means to deliver the synthetic introns into mice using novel technologies. Specifically, we are creating new nanoparticles that encapsulate these RNAs and allow them to travel in the circulation and enter MDS-disease initiating cells where they release their genetic information. As such, our proposal has the potential to develop a new therapy for a number of patients with MDS and AML while also shedding new insights into the process of RNA splicing. Moreover, the technologies we will develop to deliver RNA in mice has the potential to enable many additional therapeutic approaches which depend on genetic engineering of blood cells in patients with MDS and AML.
Program
Grant Subprogram
