# Targeting a Novel Hematopoietic Stem Cell Population in Non-Human Primates for Effective and Sustained Gene Therapy

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $684,721

## Abstract

Project Summary
Autologous hematopoietic stem cell (HSC) gene therapy is one of the most promising strategies for the treatment
of genetic diseases affecting the blood and immune system. Currently, the only curative treatment for patients
with diseases like hemoglobinopathies or immunodeficiencies is an allogeneic HSC transplant. While outcomes
with an HLA-matched sibling donor are very encouraging, most patients will not have an HLA-matched family
donor. HSC transplants from unrelated donors or partially matched donors can be associated with life-
threatening side effects especially from graft-vs-host disease (GVHD) and related infectious complications. To
avoid these complications, efforts have been made to use the patients´ own (autologous) HSCs and correct them
with either lentivirus-mediated gene therapy or gene editing. A critical problem and bottleneck, however, has
been the inability to identify and purify a “true” HSC population and therefore optimize conditions for such cells
that allow for rapid multi-lineage engraftment. A reliable strategy to determine the quality and quantity of such a
HSC population would be a major advance for high-throughput screening of ex vivo gene editing and expansion
conditions. Using our nonhuman primate (NHP) stem cell transplantation model, we have recently identified an
exclusive HSC-enriched population capable of multi-lineage short-term and long-term engraftment that is
evolutionary conserved between human and NHPs. This HSC-enriched population accounts for ~3-5% of the
entire CD34+ cell population, reducing the number of cells for gene therapy approaches by ~25-fold. Most
importantly, flow-cytometric quantification of this HSC-enriched phenotype allowed us to reliably predict
engraftment success as well as the onset of neutrophil and platelet recovery after HSC transplantation regardless
of the source, gene modification, or ex vivo expansion. Availability of this novel HSC-enriched phenotype in
combination with the ability to easily enrich for this subpopulation will help overcome current limitations of
autologous HSC gene therapy. We hypothesize that gene editing of this HSC-enriched population will improve
targeting, enhance gene editing efficiency, and increase in vivo persistence of gene-modified and corrected
blood and immune cells. Furthermore, we hypothesize that this phenotype will serve as a reliable read-out to
develop ex vivo culture conditions for the expansion of gene-modified HSCs promoting improved engraftment,
which in turn should enable us to reduce the intensity of currently used conditioning regimens for HSC gene
therapy. Evolutionary conservation of this HSC-enriched phenotype between human and NHP cells will allow us
to rapidly translate these findings to clinical HSC gene therapy studies.

## Key facts

- **NIH application ID:** 10593456
- **Project number:** 6R01AI135953-06
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** HANS-PETER KIEM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $684,721
- **Award type:** 6
- **Project period:** 2017-11-10 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593456

## Citation

> US National Institutes of Health, RePORTER application 10593456, Targeting a Novel Hematopoietic Stem Cell Population in Non-Human Primates for Effective and Sustained Gene Therapy (6R01AI135953-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10593456. Licensed CC0.

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