# Exploration of Diverse Mobile Genetic Elements for Precision Genome Manipulation

> **NIH NIH DP1** · BROAD INSTITUTE, INC. · 2020 · $1,246,000

## Abstract

The past five years have seen extraordinary advances in genome engineering technologies, yet we still lack
efficient, robust tools for precise genome manipulation, particularly the ability to insert a desired sequence at a
target site. Such tools would revolutionize our approach to treating human diseases and significantly increase the
pace of functional genetic studies throughout the biological sciences. Current approaches are focused on the
development of nucleases, such as TALENs, zinc-fingers, and Cas proteins, but there is a limit to the utility of these
enzymes and they all rely on the host endogenous DNA repair machinery. Moreover, the use of a nuclease to
achieve therapeutic gene editing requires additional efforts to safeguard against off-target mutagenic events. A
partial solution to this challenge already exists in the form of mobile genetic elements (MGEs), systems that
microbes have been using (or fighting) for millennia to achieve precise genome manipulation. We will explore the
diverse pool of MGEs and identify those with characteristics that can be leveraged for eukaryotic genome editing.
Precision genome manipulation can be broadly divided into three subcategories: insertions, deletions, and
rearrangements, each of which forms the foundation for an array of applications. Our approach will be to consider
each of these modes of operation separately to first select candidate MGEs or components of these systems
through bioinformatics analysis and extrapolating from known systems. For example, transposases and
recombinases may be harnessed for insertions, whereas the RNA-templated genome unscrambling that occurs in
the ciliates may be suitable for adaptation for genome rearrangements. Once candidates for these three modes
have been identified, we will functionally characterize them in vitro and then develop them for genome editing.
Finally, we will assess the specificity, efficacy, and safety of these novel precision genome editors in vivo. This
approach represents an innovative new direction in the development of genome engineering technology that
overcomes the reliance on nucleases by designing new, self-contained enzymatic tools that can accomplish all three
operational modes of genome manipulation. This work will complement our on-going research efforts to develop
effective delivery methods for genome engineering components. Together, these technologies will allow us to
realize the full potential of genome engineering, particularly as an avenue for treatment of human diseases.

## Key facts

- **NIH application ID:** 9997989
- **Project number:** 5DP1HL141201-04
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Feng Zhang
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,246,000
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997989

## Citation

> US National Institutes of Health, RePORTER application 9997989, Exploration of Diverse Mobile Genetic Elements for Precision Genome Manipulation (5DP1HL141201-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9997989. Licensed CC0.

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