Allison Keeler-Klunk
University of Massachusetts Chan Medical School, MA·Microbiology & Immunology
Gene therapy aims to fix a genetic disease at its source, either by delivering a working copy of a gene or by editing the faulty DNA directly. A major obstacle is the patient's own immune system, which can recognize the delivery vehicle and the editing machinery as foreign and destroy the very cells that were corrected.
- Fields
Microbiology & Immunology
Genetics
Biomedical Engineering
- Topics
gene therapy
gene editing
CRISPR-Cas9
- Grants
- 2 known grants, through Jul 2031
What they work on
- Determine how adeno-associated virus-delivered CRISPR-Cas9 provokes B- and T-cell responses against Cas9 that clear edited cells, comparing dual-AAV delivery with an AAV plus lipid nanoparticle approach that expresses Cas9 only transiently.
- Test whether pre-existing immunity to Cas9, established by prior exposure in animals, reduces the efficiency and durability of gene editing in models of alpha-1 antitrypsin deficiency.
- Test whether the less immunogenic AAV plus lipid nanoparticle strategy allows re-dosing of Cas9 to increase editing efficiency and keep edited cells long-term.
- Evaluate whether AAV-specific chimeric antigen receptor regulatory T cells, engineered suppressive immune cells, induce tolerance to both AAV capsids and Cas9 across delivery strategies and re-dosing.
- Build and validate standardized assays in mice and ferrets for innate, B-cell and T-cell responses to gene therapy, using complement and cytokine measurements, neutralizing antibody assays, ELISPOT and flow-cytometry cytokine beads.
More about the research
Within a program project on alpha-1 antitrypsin (AAT) deficiency, an inherited disorder caused by a faulty protease-inhibitor protein that leads to lung and liver disease, this work asks how immune responses limit gene editing and how they can be dampened so corrected cells last.
Why it matters
Immune attack on gene-editing components is a leading reason corrected cells disappear after treatment. By mapping these responses and testing ways to blunt them, including regulatory T cells and brief lipid-nanoparticle delivery of Cas9, this work could make gene therapies for alpha-1 antitrypsin deficiency and other inherited diseases more durable and potentially re-dosable. Standardized immune assays may also help compare candidate therapies more reliably.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Alisha Gruntman
University of Massachusetts Chan Medical School, MA·Biomedical Engineering
Breed and maintain AAT-Null-PiZ ferrets, AAT-Null and AAT-Null-PiZ mice, and wild-type mice as models of alpha-1 antitrypsin deficiency (AATD) and supply them to the program's three research projects.
David Curiel
Washington University in St Louis, MO·Microbiology & Immunology
Develop replication-defective adenoviral vectors that transduce B cells efficiently and selectively inside the body, using a "triple targeting" design intended to restrict gene delivery to the intended target cells.
Sidi Chen
Yale University, CT·Biomedical Engineering
Advance and validate MAJESTIC, a gene delivery system combining mRNA, AAV vectors and the Sleeping Beauty transposon, testing efficient and stable cargo delivery with minimal toxicity across diverse immune cell types.
The school
University of Massachusetts Chan Medical School: 29 labs on PI Pages, $350M a year on research, 55 research doctorates a year.
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