# Developing novel Type 1 CRISPR tools for gene editing therapy

> **NIH NIH R41** · GENETOBE INC. · 2024 · $293,319

## Abstract

ABSTRACT/PROJECT SUMMARY
Gene editing therapy using the Nobel Prize award-winning CRISPR-Cas9 technology promises a
permanent cure for thousands of human diseases. Up to date, CRISPR tools have enabled
dozens of FDA-approved clinical trials to tackle single-gene disorders (e.g., sickle cell disease),
infectious (e.g., HIV) and complex diseases (e.g., cancer). Yet to realize CRISPR’s full therapeutic
potential, many issues remain to be addressed.
Most of the current gene editing work uses Cas9, the RNA-guided nuclease of Type II CRISPR.
Cas9 nuclease tools suffer from several drawbacks, including low efficacy in precise gene
modification mediated by human cells’ intrinsic homology-directed repair pathway, and serious
safety concerns caused by the toxic DNA double-strand breaks (DSBs) formed at on- and off-
target sites. The non-DSB-reliant base editors (BEs) offer a path towards safer, highly-efficiency,
and precise single nucleotide editing using DNA deaminase fused to catalytically impaired Cas9.
But their targeting scope is limited by two factors, the NGG PAM required by Cas9 to be present
next to the target site, and the inflexible editing window position. Here we propose to leverage
another major branch of native CRISPR, the Type I (T1) systems, to broaden the targeting scope
for gene editing therapy.
In 2019, we pioneered T1 CRISPR-mediated genome engineering in human cells. Our ensuing
study expanded the T1 toolbox by harnessing the most compact groups of Type I editors with
diverse PAM preferences and guide orthogonality. We also found that a hidden gene product of
the T1 machinery, Cas11, must be expressed from its own eukaryotic translation initiation element
to enable robust editing by compact T1 gene editors. Built on these lines of prior work, we propose
to establish novel T1 CRISPR tools and apply them to correct disease-causing mutations.
Successful completion of Phase I work will set a solid foundation for Phase II, where we plan to
evaluate the efficacy and safety of T1 CRISPR gene therapy strategies in preclinical cell and
animal models.

## Key facts

- **NIH application ID:** 10821108
- **Project number:** 1R41GM153041-01
- **Recipient organization:** GENETOBE INC.
- **Principal Investigator:** Zhonggang Hou
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $293,319
- **Award type:** 1
- **Project period:** 2024-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821108

## Citation

> US National Institutes of Health, RePORTER application 10821108, Developing novel Type 1 CRISPR tools for gene editing therapy (1R41GM153041-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10821108. Licensed CC0.

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