# Targeted non-genotoxic hematopoietic stem cell transplant conditioning approach

> **NIH NIH K08** · EMORY UNIVERSITY · 2021 · $163,080

## Abstract

Project Summary
Hematopoietic stem cell transplant (HSCT) and gene therapy are increasingly utilized for definitive management
of disorders affecting the lymphohematopoietic compartment. Conditioning regimens are one of the critical
components HSCT. The majority of conditioning regimens used today are either based on alkylating
chemotherapy, such as busulfan, or involve varying doses of total body irradiation (TBI). These agents are
genotoxic and affect organs other than the hematopoietic compartment, leading to myriad acute and long-term
HSCT associated complications. Our overarching goal is to develop a non-genotoxic conditioning regimen
targeting hematopoietic stem and progenitor cells (HSPCs). Preliminary data from our lab indicates MPL
(thrombopoietin receptor), a critical survival signal in hematopoietic stem cells (HSCs), could be an ideal
candidate for development of HSPC-targeted HSCT conditioning approaches. Restricted expression profiles
within the hematopoietic compartment, with a higher expression in HSC when compared to the hematopoietic
progenitor compartment, make MPL a very attractive target. We have developed two strategies to target the
MPL expressing HSPC compartment. First, an immunotoxin approach, generated by conjugating MPL antibody
to a ribosomal toxin, saporin (MPL-ab-SAP), and the second, a MPL receptor engaging thrombopoietin based
CAR-T cell (TPO-CAR-T cells). We hypothesize that a conditioning agent targeting the MPL receptor will result
in selective HSPC depletion thereby creating adequate niche space to allow donor engraftment and will have
minimal risk of cytotoxicity outside the hematopoietic compartment. We will determine the mechanism, and
critical determinants of MPL-ab-SAP-mediated cytotoxicity in the HSC compartment. Then, we will determine
whether HSPC depletion by MPL-ab-SAP could be utilized as an effective conditioning strategy for HSCT and
autologous HSC-based gene therapy. The role of TPO-CAR-T cells as an HSCT conditioning will also be studied.
The K08 Award will be used to protect my time for research, help broaden my research skills and knowledge,
and provide an outstanding basis for a career in basic and translational HSCT and gene therapy. This mentored
phase of training will allow me to further integrate and build on my research skills as a physician-scientist. Over
the next five years, I will (1) gain expertise in molecular methods needed for development of therapeutic
antibodies, and gene therapy based therapeutics, (2) gain further exposure in HSC biology, transplant
immunology, and murine HSCT, (3) acquire skills in cell imaging and bioinformatics, (4) acquire skills in
translational research methodology, grantsmanship and leadership, and (5) build on my publication record and
develop research ideas for independent investigator grants. To accomplish these goals, I have developed a
well-structured training plan, and I have assembled a highly-qualified mentorship team of Dr. Spencer (expertise
...

## Key facts

- **NIH application ID:** 10242836
- **Project number:** 5K08HL141635-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shanmuganathan Chandrakasan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,080
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242836

## Citation

> US National Institutes of Health, RePORTER application 10242836, Targeted non-genotoxic hematopoietic stem cell transplant conditioning approach (5K08HL141635-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242836. Licensed CC0.

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