2021 Team Telomere Million Dollar Bike Ride Grant

Project Title: Targeting shelterin in telomere diseases

Principal Investigator: Suneet Agarwal, MD, PhD, Boston Children’s Hospital

Amount Awarded: $65,445

Lay summary: Dyskeratosis congenita (DC) is one of a spectrum of telomere biology disorders (TBDs) that affect multiple parts of the body in people of all ages. Although it is now clear that mutations impairing telomere maintenance underlie DC/TBDs, in many cases the precise mechanisms by which these mutations cause disease are not known. As importantly, how to overcome these defects to restore telomere length throughout the body remains a major challenge. In recent work, we have used cells donated by individuals affected by DC/TBDs to understand how mutations in genes encoding the telomere cap proteins, called shelterin, cause disease. In the process, we have gained new insights on how to alter telomere length in human cells. Under this award, we will test these new strategies in cells that carry a wide range of mutations that cause DC/TBDs. The overall goal of the research is to gather the evidence required to develop new small molecule therapies that apply to a broad range of genetic causes of DC/TBDs. The research to be conducted under the 2021 Team Telomere Million Dollar Bike Ride Award thereby seeks to provide a deeper understanding of disease mechanisms in DC/TBDs, and to advance novel therapeutic strategies. The Agarwal Lab is extremely grateful to the Team Telomere community and the Penn Orphan Disease Center for supporting this research.


2020 Team Telomere Million Dollar Bike Ride Grant

Project Title: Characterization of Telomere Maintenance in Tumor Models of Dyskeratosis Congenita

Principal Investigator: Judy Wong, PhD, University of British Columbia

Amount Awarded: $66,440

Lay summary: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome, with symptoms that include hematopoietic, epithelial and mucosal epithelial dysfunctions. Currently, bone marrow transplants are the only cure for DC, but their success rate is low. Even when their hematopoietic dysfunctions are adequately controlled, DC patients displayed an increased risk of developing cancers of hematopoietic and epithelial origins, at rates that were over a hundred-fold greater than the general population. DC was the first telomere maintenance disorder to be identified in humans. Accordingly, DC patients have defective telomere repair, due to mutations in the various genes involved in the telomere repair enzyme complex, telomerase. Increased cancer risks in DC patients are presumed to be a direct consequence of damaged telomeres not being repaired. Paradoxically, optimal telomere maintenance is crucial for the malignant tumor growth, and how DC tumors overcome its telomerase deficiency limitation is not currently known. Our proposal aims to provide a better understanding of the tumorigenesis process in DC. Our group is creating DC tumor cells in the laboratory, using patient materials from the Inherited Bone Marrow Failure Syndrome cohort, collected by our clinical collaborators at the NCI. We will compare the success rate of creating tumors (oncogenic transformation) in cells obtaining from DC patients and healthy donors.  Clonal DC tumors will be characterized for their telomere maintenance activity, and queried for the molecular mechanisms on overcoming their genetic limitations on telomere repair to achieve immortal growth. Successful implementation of this procedure will establish DC tumor models for future research, and inform screening and therapeutic guidelines.


2019 Team Telomere Million Dollar Bike Ride Grant

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

Principal Investigator: Daria Babushok MD, PhD, University of Pennsylvania
Co-Principal Investigator: Bradley Johnson MD, PhD, University of Pennsylvania and Timothy Olson MD, PhD, 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.


2018 Team Telomere Million Dollar Bike Ride Grant

Project Title: Pharmacologic rescue of telomere defects in dyskeratosis congenita

Principal Investigator: Brad Johnson MD, PhD and Chris Lengner PhD, 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.


2017 Team Telomere Million Dollar Bike Ride Grant

Project Title: Small molecule modulators of telomerase as novel treatments for Dyskeratosis Congenita

Principal Investigator: Suneet Agarwal, MD, PhD, 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.


2016 Team Telomere Million Dollar Bike Ride Grant

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

Principal Investigator: Suneet Agarwal, MD, PhD, 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.