2020 Team Telomere Million Dollar Bike Ride Grant

Project Title: Pre-malignant Clonal Evolution in Telomere Biology Disorders (TBD)

Principal Investigator: Daria Babushok M.D. Ph.D., University of Pennsylvania

Co-Principal Investigator: Bradley Johnson M.D. Ph.D., University of Pennsylvania and Timothy Olson M.D. Ph.D., Children’s Hospital of Philadelphia

Amount Awarded: $62,664

Lay summary:

Telomere biology disorders (TBD, also known as dyskeratosis congenita or DC) are caused by a defect in one of the genes that protect the ends of chromosomes called telomeres. Because of defective telomere maintenance, the ends of chromosomes in TBD patients become critically short, causing premature activation of cellular pathways associated with aging, which normally protect us by preventing replication of cells with damaged DNA. One of the most severely affected organs in TBD patients is the bone marrow. Failing bone marrow causes low blood counts and puts TBD patients at an increased risk of developing blood cancers such as acute leukemia and myelodysplastic syndrome (MDS). This research funding will allow us to determine the genetic changes that precede blood cancer development in TBD patients. We will specifically assess whether the disruption of pathways associated with aging and DNA damage is associated with precancerous changes in TBD.  The results of these studies will help us to identify important genetic alterations that could serve as predictors of precancerous changes in the patients’ bone marrow and as new targets for personalized therapies.

Principal Investigator: Suneet Agarwal, Boston Children’s Hospital

Amount Awarded: $100,373

Lay summary:

There are no treatments for myriad problems faced by patients with dyskeratosis congenita (DC). We recently discovered how a new gene mutation, PARN, causes DC. That research revealed to us new and unexpected ways to control telomere length, which is defective in DC patients. Based on this information, we discovered molecules that are able to lengthen telomeres in cells from patients with DC. Under this award, we are going to rigorously test these molecules and study telomere-lengthening and other effects in patients’ cells. This research funding is important and timely because the experiments are directly aimed at developing new drugs for patients with DC.

Pharmacologic rescue of telomere defects in dyskeratosis congenita

Principal Investigator: Brad Johnson and Chris Lengner, University of Pennsylvania

Amount Awarded: $50,000

Lay summary: 
The primary problem underlying the diseases suffered by people with dyskeratosis congenita (DC) is a failure of telomerase to maintain telomeres in a functional, i.e. “capped” state. This failure is secondary to mutations that partially compromise the ability of telomerase to lengthen telomeres. It is not yet possible to repair these mutations in all the affected cells of people with DC, and so instead of taking a genetic approach to DC therapy, we are investigating a potential pharmacological approach that is based on our recent discovery of a positive feedback loop between telomere capping and the activity of the Wnt signaling pathway. Wnt signaling is one way that different types of neighboring cells can communicate with one another, and it is particularly important in the support of tissue stem cells that are critical for tissue health. We found that when telomeres are capped, Wnt signaling is active, which in turn, feeds back to support continued telomere capping. This virtuous cycle breaks down when telomeres become prematurely shortened in DC, and indeed becomes vicious as the decline in Wnt signaling leads to further telomere uncapping. We reported recently that pharmacologic enhancement of Wnt signaling (e.g. using inhibitors of an enzyme called GSK3) can restore telomere capping and stem cell and tissue health in models of DC intestinal defects. We are now testing the applicability of this approach in other tissues, including lung and liver. Of particular note, we have recently established Wnt pathway defects related to type II alveolar epithelial stem cell dysfunction in a human cultured lung organoid model derived from induced pluripotent stem cells bearing DC-causing mutations. Moreover, GSK3 inhibition rescues these lung epithelial defects, supporting the potential utility of Wnt pathway agonists in DC therapy.

A multi-center, prospective, minimal intensity BMT trial for dyskeratosis congenita

Principal Investigator: Suneet Agarwal, Boston Children’s Hospital

Amount Awarded: $50,000

Lay summary:
Bone marrow transplantation (BMT) is a life-saving therapy for many blood diseases, but the chemotherapy and radiation typically used in BMT cause life-threatening complications. For patients with the rare disease dyskeratosis (DC) who require BMT to cure their failing blood system, the toxicity and risks of BMT can be even more severe. We are conducting a clinical trial that asks whether DC patients can undergo BMT without using traditional “DNA-damaging” chemotherapy and radiation, in order to reduce the toxicity of the procedure and improve survival. The idea that this might work comes from an emerging understanding of the genetics and biology of DC. So far, a series of DC patients treated at one institution have successfully undergone BMT on this trial, making them the first group to obtain a cure for their failing blood systems without exposure to DNA damaging radiation and chemotherapy. Now, we aim to expand this trial to other major centers in the United States, as the first prospective multi-center BMT trial for DC. The 2016 Million Dollar Bike Ride Pilot Award from Team Josh and the DCO Riders will enable multi-center expansion of this clinical study, which promises to change the approach and outcome of BMT for DC patients.