MEMP PhD Thesis Defense: Colin Hemez

Advancing the development and application of genetic medicines

Precision gene editing offers the promise of permanently correcting alleles that cause disease in the genomes of affected individuals with one-time treatments. Making this promise a reality has been a major objective of molecular biology and genetics since the first descriptions of the mutations that cause cystic fibrosis—the first for any genetic disease—were reported in 1989. My doctoral work has focused on developing and applying precision gene editing technologies to correct cystic fibrosis-causing pathogenic mutations at increasing scales.

In this thesis seminar, I describe the systematic optimization of prime editing—a CRISPR-based precision gene editing technology—to efficiently correct CFTR.F508∆, a three-nucleotide deletion that is the predominant cause of cystic fibrosis. By combining six recent advances in prime editing, we increased CFTR.F508∆ correction efficiency from <0.5% in model cell lines to 58% in therapeutically relevant immortalized bronchial epithelial cells. In primary airway cells derived from people with cystic fibrosis, our optimized editing strategy enabled 25% precise correction of CFTR.F508∆, restoring CFTR ion channel function to >50% of wild-type levels—comparable to treatment with the standard-of-care modulator drug combination elexacaftor-tezacaftor-ivacaftor. I then summarize the exploration of helper-dependent adenoviral vectors, engineered virus-like particles, and lipid nanoparticles for the delivery of prime editors to both differentiated and undifferentiated primary airway cells as well as to human bronchial epithelial cell lines. These efforts demonstrated prime editing-mediated CFTR function restoration via therapeutically relevant delivery vectors, helping to define the editing thresholds needed to achieve therapeutic effect in airway epithelia. Finally, I present efforts to leverage self-targeting lentiviral screens to accelerate the optimization of prime editing formulations for therapeutic applications. We use these tools to screen thousands of pegRNAs for 117 cystic fibrosis-causing alleles that do not respond to modulator therapies in multiple cell types. We also describe adaptive triaging, an active learning method that enables iterative optimization of pegRNA silent edit strategies in an allele- and cell type-agnostic manner.

The approach to therapeutic prime editor optimization I describe in this thesis could be applied to numerous other diseases with diverse genetic origins or to collections to genetic diseases that manifest with similar pathologies, accelerating the development of genetic therapeutics as ensembles of medicines.

Thesis Supervisor:
David R. Liu, PhD
Thomas Dudley Cabot Professor of the Natural Sciences
Professor of Chemistry & Chemical Biology, Harvard University 

Thesis Committee Chair:
Adam E. Cohen, PhD
Professor of Chemistry and Chemical Biology and of Physics, Harvard University

Thesis Readers:
Katie Galloway, PhD
W. M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering
Assistant Professor of Chemical Engineering, Massachusetts Institute of Technology

Taekjip Ha, PhD
George Yancopoulos in honor of Frederick Alt Professor
Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

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Zoom Invitation
Colin Hemez is inviting you to a scheduled Zoom meeting

Topic: Colin Hemez MEMP PhD Thesis Defense
Time: Tuesday, November 25, 2025, 3:00 PM Eastern Time (US and Canada)

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