# Mcl-1 inhibition for induction of hematopoietic chimerism without nonselective myeloablative treatments in nonhuman primates

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $245,795

## Abstract

PROJECT SUMMARY / ABSTRACT
 Hematopoietic stem cell transplantation (HSCT) is potentially applicable to various medical settings
beyond current standard of care (SOC), such as therapy for autoimmune disease, gene modification or induction
of transplant tolerance. However, its wider clinical application is currently hampered by the myeloablative and
genotoxic conditioning required for successful HSC engraftment. Such conditioning generally includes non-
selective myeloablative treatments, such as total body irradiation (TBI), cyclophosphamide, or fludarabine that
are associated with serious systemic side-effects including pancytopenia, infections, infertility, and, not
infrequently, death.
 To develop a safer conditioning regimen without such myeloablative and genotoxic consequences, a
therapeutic modality that selectively depletes host hematopoietic stem cells (HSCs) and opens a physical space
in bone marrow (BM) niches needs to be identified. Based on murine studies, we hypothesized that selective
inhibition of antiapoptotic B cell lymphoma 2 (Bcl-2) may effectively induce apoptosis of HSCs, thereby promoting
HSC engraftment without need for non-selective myeloablative treatments. Indeed, a selective Bcl-2 inhibitor,
Venetoclax, appeared significantly promotes hematopoietic chimerism by depleting HSCs in BM niches in non-
human primates (NHPs). Although this was achieved without severe pancytopenia, some TBI was still required
to induce chimerism as depletion of HSCs was limited with Venetoclax alone. Since Mcl-1, another anti-apoptotic
protein, has recently been reported to be more critical for survival of HSCs, we further hypothesize that inhibition
of Mcl-1 alone or in combination with Bcl-2 will more effectively deplete host HSCs, thereby creating sufficient
space in BM niches and allowing optimal allogeneic HSC engraftment without any myeloablative treatment. The
results of preliminary study have been encouraging, where successful induction of hematopoietic chimerism was
achieved without TBI by combining low dose Mcl-1 inhibitor and Venetoclax. The main objective of this R21
project is to test whether Mcl-1 inhibition alone or with Bcl-2 co-inhibition can consistently and safely induce
hematopoietic chimerism without TBI in MHC mismatched NHP HSCT. Chimerism induced by this approach will
then be tested for induction of renal allograft tolerance. Since there is only limited information available on the
role of different anti-apoptotic Bcl-2 proteins in primates, we will also characterize the intrinsic apoptotic pathways
of HSCs in NHPs in this study.

## Key facts

- **NIH application ID:** 10288014
- **Project number:** 1R21AI163806-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** TATSUO KAWAI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $245,795
- **Award type:** 1
- **Project period:** 2021-05-20 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288014

## Citation

> US National Institutes of Health, RePORTER application 10288014, Mcl-1 inhibition for induction of hematopoietic chimerism without nonselective myeloablative treatments in nonhuman primates (1R21AI163806-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288014. Licensed CC0.

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