TITLE: Novel Small Molecule Therapeutics for Genetic Lung and Blood Diseases
TYPE OF AWARD: Drive
CLINICAL AREA:  Small Molecule
INSTITUTION: Boston Children’s Hospital
DESCRIPTION: Telomere diseases encompass a spectrum of rare and fatal syndromes that are caused by mutations in genes regulating telomere biology. These include the severe childhood blood disorder dyskeratosis congenita (DC) and later-onset diseases such as pulmonary fibrosis (PF). Despite progress in gene and pathway discovery in telomere diseases in the past two decades, there has been no translation of this knowledge into therapies and there are no curative treatments. In our recent work identifying genetic lesions in DC and PF patients, we defined a new pathway regulating telomere maintenance, which we now aim to target for the treatment of DC, PF and other degenerative disorders.
We discovered components of the post-transcriptional machinery that regulate accumulation of the non-coding telomerase RNA (TERC), which is critical for telomerase function and is disrupted in several genetic forms of telomere diseases. We found that inhibiting one of these factors, PAPD5, restores TERC and telomere maintenance in induced pluripotent stem cells (iPSCs) from patients with DC or PF. We have discovered small molecule modulators of this enzyme that we now aim to develop into therapeutics. The goal of this project is to advance a small molecule inhibitor strategy targeting PAPD5 to clinical lead stage. If successful, this strategy will provide a novel approach to manipulate telomerase for the treatment of genetic lung and blood diseases caused by defective telomere maintenance, and potentially other degenerative disorders.