Novel Therapeutics for Bone Marrow Failure Disorders Due to Telomere Exhaustion
Abstract
The overall goal of this project is to understand molecular pathways leading to bone marrow failure (BMF) caused by impaired telomere maintenance, and exploit them for therapy. The proposal builds on our recently published work that for the first time defines non-coding RNA pathways and novel enzymatic targets regulating humantelomerase. In preliminary work, we identified a hit molecule in a high-throughput screen that increases telomerase activity. Here, we propose to study how manipulation of these pathways using novel small molecule analogs of the hit compound impact telomere biology and hematopoiesis in stem cells, including those from patients with BMF disorders caused by telomere dysfunction such as dyskeratosis congenita (DC). We find that analogs of the hit molecule show enhanced ability to augment telomerase and telomere length in patient cells. Such molecules restore telomerase RNA processing and do not adversely impact hematopoietic stem cell function in vitro. Taken together, this work advances novel therapeutic strategies for BMF disorders associated with telomere exhaustion.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1139918
Entities
People
- Suneet Agarwal
Organizations
- Boston Children's Hospital