# Core B: Genome Engineering Core

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2022 · $166,471

## Abstract

Abstract Core B. Quantifying outcomes of genome modification
Core B will track the nature and consequences of genome modifications carried out in
Projects 1, 3 and 4, and use these data to design improved reagents for CART genome
modification. Core B will analyze several types of genome modification as dictated by
the needs of each project. Integration of lentiviral vectors necessarily disrupts the host
cell locus at the site of integration. We and others have found that insertional
mutagenesis by vectors used to deliver CARs can be associated with altered cell
growth, which has resulted in clinical adverse events, but also clinically favorable clonal
expansions that have bolstered therapeutic effects. The core will use these data to
identify genes and pathways to manipulate to optimize CART expansion and
persistence. Vector integration also marks each transduced cell uniquely, allowing
tracing of the partitioning of descendant cells, information useful in tracking outcomes
and understanding mechanisms of possible adverse events. Cleavage of the host
genome using targeted nucleases is also an effective means of achieving genome
modification; however, off-target cleavage and associated deletions are safety
concerns. The core will monitor off-target cleavage using our iGUIDE technology.
Lastly, in protocols where multiple sgRNA/CAS9 complexes cleave multiple targets in a
single cell, nuclease cleavage at multiple sites can result in rejoining of DNA ends in a
“swapped” fashion, causing chromosomal translocations. Core B will monitor molecular
outcomes in each of these categories to allow optimization of reagents, assessment of
safety, and scoring of cell function.

## Key facts

- **NIH application ID:** 10450647
- **Project number:** 5U19AI149680-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Frederic D Bushman
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $166,471
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450647

## Citation

> US National Institutes of Health, RePORTER application 10450647, Core B: Genome Engineering Core (5U19AI149680-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450647. Licensed CC0.

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