Novel small molecules to treat degenerative lung and blood diseases

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PROJECT SUMMARY/ABSTRACT. Telomere diseases encompass a spectrum of rare and fatal syndromes caused by mutations in genes regulating telomere biology. These include the severe childhood blood disorder dyskeratosis congenita (DC) and later-onset lung diseases such as pulmonary fibrosis (PF). Despite progress in gene and pathway discovery in the past two decades, there has been no translation of this knowledge into therapies, and there are no curative treatments. Central to the pathogenesis of telomere diseases is disruption of telomerase, the ribonucleoprotein complex that replenishes telomeres in human cells. The long-term goal of this project is to therapeutically restore the long non-coding RNA component of telomerase, TERC, which is dysregulated in DC, PF and other telomere diseases. The public/health/relevance is broad. TERC levels determine telomerase activity levels in human stem cells, and in turn the regenerative capacity of tissues over the lifespan. Common genetic variants in TERC are associated with cardiovascular and pulmonary diseases. Mutations that disrupt TERC cause Mendelian disorders presenting across the age spectrum including bone marrow failure and chronic lung diseases. Recent genetic studies in DC and PF shed new light on factors that might be targeted to manipulate TERC, specifically post-transcriptional RNA processing factors. Based on these new insights, the goal of this project is to develop small molecule inhibitors to an RNA polymerase that destabilizes TERC, called PAPD5. The central hypothesis is that there is a therapeutic window wherein PAPD5 inhibition can restore TERC levels and telomerase function. If successful, this strategy may provide a novel class of systemic therapies for telomere diseases. The central hypothesis will be tested by pursuing two Specific Aims: (1) Design, synthesize, and characterize improved PAPD5 inhibitors, and (2) Identify a lead series of PAPD5 inhibitors for further pre-clinical development. The aims are responsive to the NHLBI Catalyze grants program, to identify a lead compound series toward therapeutic development for lung and blood diseases. The proposal takes advantage of an innovative pipeline that spans high-throughput screening to in vivo efficacy, enabling rigorous pre-clinical evaluation of novel PAPD5 inhibitors. Under the first aim, medicinal chemistry, biochemical assays, and patient-derived induced pluripotent stem cell (iPSC) models will advance small molecule PAPD5 inhibitors. Under the second aim, conventional lead optimization assays will be coupled to a novel hematopoietic stem cell xenotransplantation model, to enable in vivo assessment of telomere elongating capacity by PAPD5 inhibitors in disease-relevant human stem cells. The approach is innovative because it leverages new methods and insights to allow a critical shift in focus from nucleic acid delivery to targeting a non-coding RNA biogenesis pathway, as a means of therapeutically modulating telomerase. The proposed research is significant, because it is expected to yield strategies to manipulate telomerase to treat a broad range of degenerative lung and blood disorders, for which there are no curative therapies.