# In vivo gene editing of hematopoietic stem and progenitor cells

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2021 · $417,500

## Abstract

PROJECT SUMMARY
central goal of this proposal is to develop and provide proof-of-concept testing for an in situ genome
editing platform to accomplish programmed gene modification (including sequence deletion and sequence
insertion) in endogenous genes of hematopoietic stem and progenitor cells (HSPCs). If successful, our studies
could provide an alternative to current transplantation-based paradigms being pursued in both academia and
industry to achieve curative therapy for genetic blood diseases, including Sickle Cell Disease (SCD) and β-
The thalassemia. While such strategies, in which allogeneic or ex vivo modified autologous HSPCs are used to
reconstitute the patient's blood forming system with hematopoietic progenitors that
produce functional, non-sickling β-globin, represent a reasonable and even promising approach for rescuing defective hemoglobin
production, they carry inherent risks from transplantation-associated toxicities, and have suffered from the ongoing challenge of achieving sufficient engraftment to support therapeutic hematopoietic reconstitution in animal models and patients.
For these reasons, we choose here to pursue a radically different approach.
The overall hypothesis driving this work is that by using in vivo functional gene modification strategies we can
develop a broadly applicable approach to correct the phenotypic and functional defects of erythrocytes in both
SCD and β-thalassemia. Our experimental approach will build on our extensive preliminary data and novel
resources documenting the in vivo transduction of HSPCs by adeno-associated viruses (AAVs) carrying
genome modifying nucleases and adapt this system to enable sequence-specific homology directed
recombination (HDR) at the β-globin locus. We will then test the therapeutic utility of this approach using
disease-relevant SCD model mice. Success in these pre-clinical studies will provide critical proof-of-concept
data to support follow on studies to investigate this approach as a different, and possibly safer and more
accessible, clinical path for achieving therapeutic gene editing in SCD, β-thalassemia and possibly other
hematologic disorders. In addition, this work may open new avenues for research, enabling future applications
of this technology for the experimental interrogation of gene function in endogenous HSPCs, something that
currently requires the generation of new transgenic mice or use of transplant systems that irrevocably alter the
host environment and lead to oligoclonal hematopoiesis that is not normally seen in the blood system in young,
healthy animals. Our proposed studies thus hold promise for both basic and translational impact.

## Key facts

- **NIH application ID:** 10106652
- **Project number:** 5R01HL135287-04
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** AMY JO WAGERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2018-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106652

## Citation

> US National Institutes of Health, RePORTER application 10106652, In vivo gene editing of hematopoietic stem and progenitor cells (5R01HL135287-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10106652. Licensed CC0.

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