Mitochondrial DNA Deletion disorders
Bone Marrow Failure
Certain genetic disorders cause widespread disease in the body, but the principle reason for illness and death in early childhood is failure of the blood system. We would like to study these genetic blood disorders by “turning back the clock” – using new technology in stem cell biology to take skin cells from patients with genetic blood disorders and return them to an embryonic-like state, wherein they regain the ability to form any type of cell in the body. We believe that studying this process of going back to an embryonic-like state, and then seeing how the cells develop into different tissues (blood cells, muscle, nerves, etc.), will lead to a better understanding of what is going wrong in cells carrying these disease-causing mutations. We hope that the knowledge gained through this work will provide innovative therapies – using novel medications or perhaps even one’s own cells - for patients with genetic blood disorders, and will help develop similar strategies for patients with other rare disorders.
Current research topics include:
Development and characterization of small molecules to treat telomere biology disorders
Uncovering the molecular biology of telomere disease causing variants with unknown mechanisms using induced pluripotent stem cells (iPSCs)
Mitochondrial genome engineering
Characterization of heteroplasmy dynamics in inherited mitochondrial disorders
Unbiased genome wide discovery of new pathways involved in telomere length control
Gene editing approaches to cure inherited bone marrow failure syndromes
Methods to measure telomere length in single cells
Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells
Nagpal et al. Cell Stem Cell 2020
In this issue, Nagpal et al. show telomere restoration using small molecules in patient stem cells. In the image, the personified chromosome is balding, representing telomere shortening with age. He applies BCH001, a small molecule PAPD5 inhibitor, envisioning a future self with restored telomeres (and hair). Cover by Jack Mannherz.