Development of Novel Therapies for Patients with Telomere Biology Disorders

This roundtable sought to set concrete, achievable milestones in the development of novel therapies and curative options for patients with TBDs.

What does a “cure” look like for patients? Participants explored multiple perspectives on what constitutes a cure for TBDs:

• Resolution of disease: A single-use intervention (analogous to antibiotics) that targets telomere length and integrity in the whole body
• Primary prevention: Early mutation detection to prevent/postpone disease onset
• Symptom management: Treatments that optimize outcomes and quality of life even when the underlying genetic cause cannot be corrected
• Organ-specific interventions: Targeted therapies for individual manifestations (e.g., bone marrow failure, pulmonary fibrosis, liver disease)

Critical considerations for patients:

• Quality of life is paramount alongside longevity
• Cures may be gene-specific or symptom-specific, rather than universal
• Communication with patients must be thoughtful
• Irreversible damage may persist even with effective treatments
• Timing of intervention matters

Key problems to tackle

Delivery and targeting:

• How do we deliver treatments to reach all relevant tissues simultaneously?
• Can approaches proven in one organ system (e.g., ex-vivo HSC editing for bone marrow) be adapted for others (lung, liver)?

Understanding disease biology:

• There is a severe gap in knowledge in TBD natural history, which would define baseline trajectories across diverse individuals
• We need better characterization of rare mutations and genetic diversity, and how these relate to disease manifestations
• From a molecular perspective: (1) How can we restore telomere length and integrity? (2) How can we modulate DNA damage response signaling from short or unhealthy telomeres?

Measuring treatment efficacy:

• Current biomarkers (average telomere length) are insensitive due to differences between individual cells, and are not applicable to individual organ systems
• Clinical endpoints vary by organ system
• FDA standards require concrete clinical outcomes
• We need a consensus on meaningful endpoints across trials and organ systems

How should we invest time and effort now?

Research infrastructure:

• Combine data from multiple clinical trials to identify patterns and refine endpoints
• Develop biobanks with accessible, clinically relevant tissue samples
• Establish longitudinal data on healthy individuals for comparison

Regulatory strategy:

• Engage FDA early through mechanisms like CDER Patient-Focused Drug Development
• Build consensus on clinical endpoints that balance feasibility with regulatory acceptance
• Create standardized biomarker panels for use across future studies

Scientific priorities:

• Investigate telomere profiling analysis to track shifts in telomere length distributions within cell subsets
• Research robust systematic and organ-specific biomarkers that can be used to monitor improvement and clinical outcomes in future Phase II clinical trials

Looking forward, we hope to:

1. Complete comprehensive natural history studies that define disease trajectories across genetic variants and organ systems
2. Establish clinical endpoints with proven associations to patient outcomes
3. Develop and standardize robust biomarkers for monitoring disease progression and treatment response across organ systems
4. Increase testing to increase the body of knowledge for TBDs