# Development, characterization and application of CRISPR/Cas9 gene drive technologies and related active genetic elements to benefit research and society at large

> **NIH NIH DP5** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $387,500

## Abstract

PROJECT SUMMARY
On the morning of December 18th 2014, I arrived in the laboratory early to check on my experiment — what
ended up being the first proof that the Mutagenic Chain Reaction (MCR) functioned as a highly efficient
CRISPR/Cas-based gene-drive system in fruit flies [1]. I later built a similar, albeit more complex, MCR
construct in mosquitoes, that was tested in collaboration with the James group (UCI) [2]. As was the case for
the fruit fly element, the mosquito MCR propagates with exceptional efficiency (99.5%) via the germline. During
this process, my advisor Ethan Bier and I expanded the concept of `active genetics' [4] to a family of genetic
elements that actively copy themselves onto the companion chromosome (as in the MCR). These elements
bypass the constraints of Mendelian inheritance, thereby potentially overcoming current limitations in
laboratory experiments. Gene drive systems can be used to combat vector-borne diseases thereby benefiting
global public health (e.g., malaria eradication), as well as to restore native ecosystems (e.g., suppress invasive
species populations). Although I am interested in future applications in diverse fields, during the award period I
will focus on deepening the knowledge on the mechanism of action of active genetic elements in the fruit fly.
Here I propose to build and characterize in Drosophila melanogaster three categories of active genetic
elements: (1) Full MCR-gene drives, (2) Split, “transcomplementing-MCR”, an alternative that could offer
advantages when performing population modification in the wild, (3) Reversal constructs to stop, limit or
reverse the spread of a Cas9-based gene drive in the wild.
1) I will examine the basis for the extraordinary efficiency of our existing gene drive technology and refine its
 functionality for future field applications. Several gene drives, based on MCR technology, will be developed
 in the fruit fly. Different regulatory regions will be identified to drive the expression of the Cas9 nuclease in
 the most effective time during development while assuring its restriction to germline cells.
2) I will build and test trans-complementing-MCRs in which the two primary MCR components (Cas9 and
 gRNAs) are split in two separate transgenic constructs. Each component individually would not generate
 inheritance bias; only when combined will these elements reconstitute a gene drive arrangement. This
 technology could be used in population suppression schemes where a full gene drive, purposely affecting
 fitness, would otherwise render problematic the amplification of the laboratory population to the levels
 necessary for field release.
3) I will develop reversal constructs that can counteract the spread of a Cas9-based gene drive construct in a
 population. I will test two different types of such constructs: the first one acts by cutting out and replacing
 the gene drive at the same locus at which it is inserted; the second type is located in a different location in
 the genome, bu...

## Key facts

- **NIH application ID:** 9989922
- **Project number:** 5DP5OD023098-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** VALENTINO MATTEO GANTZ
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2016-09-19 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989922

## Citation

> US National Institutes of Health, RePORTER application 9989922, Development, characterization and application of CRISPR/Cas9 gene drive technologies and related active genetic elements to benefit research and society at large (5DP5OD023098-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989922. Licensed CC0.

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