Session 6: Emerging Field Innovations and Advancements
Overview
Session 6 opened with a scientific overview from Dr. Tracy Bryan of Children’s Medical Research Institute, who reminded the room just how many proteins and pathways work together to keep telomeres, the protective caps at the ends of our chromosomes, intact. At the center of it all sits telomerase, which is built from the protein TERT and its RNA partner hTR, that actively rebuilds these caps. Nearly every talk that followed circled back to one central question: how can we restore telomerase function, or better detect when it isn’t working, for people living with telomere biology disorders (TBDs)?
The session opened with Sean Tully’s story of turning grief and determination into research funding, which set the tone for a session built around finding real paths forward for patients. Researchers also described a striking range of possible strategies: a small molecule therapy already being tested in a Phase I clinical trial, a newly discovered biological pathway that might switch telomerase back on after its turned off, an experimental gene editing approach that is designed to correct a common mutation hotspot, a large scale effort to finally interpret the genetic variants doctors find in patients, a new sequencing technology that reads telomeres in far greater detail than before, and basic laboratory work that reveals how the RNA piece of telomerase must fold correctly in order to work at all.
Together, these talks showed a field advancing on multiple fronts at once: some ideas are already being tested in patients, while others are still years from the clinic. What united them was a shared commitment to understanding telomerase, in ever finer molecular detail, so that today’s incomplete answers and laboratory findings can become tomorrow’s treatments.
Highlights from Each Talk
Thymidine Trial Update: Dr. Helen Reed, Boston Children’s Hospital
Dr. Helen Reed gave an update on the Nucleoside Therapy and Telomere Biology Disorders Phase I trial, known as the thymidine trial. Current treatments for blood complications in TBDs are limited, and no existing drug directly targets telomerase itself. Lab research found that thymidine, a DNA building block, increased telomere length in human cell lines and patient-derived stem cells, which lead to this open-label safety trial in patients ages 1 to 70. As of the summit, 29 of a target 36 participants had enrolled with no serious side effects reported, and full results are expected by summer 2027.
Identification of New Pathways to Restore Telomerase Function in Telomere Biology Disorders: Dr. Luis Batista, University of Utah Health
Dr. Luis Batista shared lab research on an unexpected link between telomerase and DNMT3A, a gene commonly mutated in clonal hematopoiesis, which is a pre-cancerous condition in which blood stem cells with certain mutations gradually take over and outnumber other cells. His team found that losing DNMT3A activity increases telomerase activity and telomere length in mouse and human cells, and in telomerase-deficient mice; removing DNMT3A therefore partially restored stem cells’ ability to keep producing blood. Early experiments in human stem cells that carried a common dyskeratosis congenita mutation showed a similar effect. Dr. Batista sees this as a genuinely new pathway, though one that needs clinical caution due to DNMT3A’s own cancer links, and it remains confined to the lab for now.
Developing Therapies in Rare Disease: Dr. Daniel Bauer, Boston Children’s Hospital
Dr. Daniel Bauer described early lab work exploring whether gene editing, technology that lets scientists directly rewrite DNA, could one day treat TBDs. His team focused on TINF2, a gene in which nearly all disease-causing mutations associated with the gene occur in one small region, and tested a “prime editing” approach that was designed to correct that entire region regardless of a patient’s specific mutation. In lab experiments, combining their method with drugs that block a competing DNA repair pathway achieved high precision editing, which was confirmed by genome-wide sequencing, and the editing also worked in “resting” cells; this is important since most blood stem cells aren’t actively dividing, but should be edited in case they do. Dr. Bauer was clear this remains preclinical, with much more testing needed before any human trials.
Functional Atlas of TERT Variants: Dr. Christopher Reilly, Dana-Farber Cancer Institute
Dr. Christopher Reilly tackled a familiar problem: genetic testing often finds a change in the TERT gene, but doctors frequently can’t say whether it causes disease: this occurs in roughly 60% of TERT variants in TBD patients and 96% of variants in general population databases. His team built a functional atlas testing over 1,100 TERT variants in a lab system measuring telomere length, and sorting them by severity. Severely impaired variants proved far more common in the general population than expected, occurring close to 1 in 400 people, and impairment tracked with shorter telomeres and higher risk of TBD-related conditions. The atlas is meant to help doctors interpret results with more confidence.
NanoTelSeq: Single Telomere Analysis by Long Read Nanopore Sequencing Improves Diagnosis of Telomere Biology Disorder Patients and Risk Assessment in Asymptomatic Mutation Carriers: Dr. Yehuda Tzfati, The Hebrew University of Jerusalem
Dr. Yehuda Tzfati challenged the field to look beyond simple average telomere length, arguing it doesn’t fully capture what makes a telomere functional, since some TBD patients have telomeres that aren’t especially short while some healthy people have short telomeres without disease. His team developed NanoTelSeq, which uses nanopore sequencing to examine individual telomeres in far greater detail than standard tests, and measures the share of critically short telomeres, which is especially informative for identifying TBD patients. The method works across tissue types and small samples. He hopes to release the analysis software soon, believing this detailed view could improve diagnosis and help assess risk in relatives who carry a mutation but have no symptoms yet.
Induced Pluripotent Stem Cells Offer Unique Insights into Telomerase RNA Folding: Eva Edelson, University of California, Santa Cruz
Eva Edelson presented her thesis research on hTR, the RNA molecule that forms an essential structural part of telomerase alongside the TERT protein, and which must fold into a precise architecture to work. Using a technique that maps how RNA folds inside living cells, she found that in standard lab cell lines, about 85% of hTR folds correctly while 15% misfolds into a non-functional shape. In induced pluripotent stem cells, cells reprogrammed to behave like stem cells, essentially all hTR folded correctly in healthy cells, but in cells carrying either of two dyskeratosis congenita mutations, a meaningful portion misfolded, a possible explanation for how these mutations cause disease by impeding the ability of these cells to make enough telomerase to maintain telomeres.
What This Means for the Field
Session 6 showed just how many angles researchers are working from at once to understand, and eventually treat, telomere biology disorders. Some approaches, like the thymidine trial, are already being tested directly in patients and are focused right now on establishing safety before any conclusions can be drawn about effectiveness. Others, like Dr. Batista’s DNMT3A findings and Dr. Bauer’s gene editing work, are still confined to mouse models and cell lines, representing genuinely new biological pathways and tools that could open future treatment options, but that remain years away from clinical trials.
At the same time, several talks made clear that better tools for understanding and diagnosing TBD are just as important as new treatments. Dr. Reilly’s functional atlas of TERT variants and Dr. Tzfati’s NanoTelSeq method both aim to close a real gap: today, many patients carry genetic changes that doctors cannot yet interpret, or have telomere lengths that don’t tell the whole story. Eva Edelson’s work on how the RNA component of telomerase folds shows that even the most fundamental questions about how this enzyme assembles still carry direct relevance for understanding disease.
