# Cellular and Molecular Studies of Bone Marrow Transplant

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $2,394,938

## Abstract

OVERALL ABSTRACT
Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic
hematopoietic cell transplant (HCT) and prevents this curative therapy from wider application in cancer
patients. This P01 consists of three projects and two cores and its goal is to significantly reduce GVHD
by: (1) elucidating its basic biology; (2) developing new laboratory strategies to predict its long term
outcomes; and (3) translating these insights into novel therapeutic strategies in Phase 2 clinical trials.
Gastrointestinal (GI) GVHD is the target organ that is most resistant to steroid treatment and acute GVHD
in the GI tract accounts for the vast majority non-relapse mortality. The focus on mechanisms of damage
to the GI crypt during GVHD and enhancing its regeneration unifies all three projects during this cycle of
the P01. Project 1 investigates the key bioenergetic pathways in intestinal stem cells (ISCs) that are
altered during GVHD. Preliminary data have identified a profound defect in the key mitochondrial enzyme
Succinate Dehydrogenase A (SDHA) that is specifically depleted by the T cell attack on intestinal epithelium
during GVHD. Project 1 will analyze the role of SDHA in ISCs and will also evaluate SDHA expression in
human GI biopsies in a collaboration study with Project 2. Project 2 also explores the regeneration of
crypts by ISCs during GVHD, focusing on the key enzyme receptor-interacting protein kinase I (RIPK1)
that controls the inflammatory cell death pathway. A collaboration with Genentech leverages their deep
expertise in this field to explore RIPK1 biology in animal models and human samples. Project 2 shares a
subaim with Project 1 to investigate the interactions of SDHA with the RIPK1 pathway in ISCs during
GVHD. Project 3 translates insights from the preclinical projects into two highly innovative clinical trials.
The first trial will test a Genentech RIPK1 inhibitor in a Phase 2 trial. The second trial uses novel real-
time monitoring with serum biomarkers to identify a group of patients with minimal GI crypt damage who
can be safely treated with much lower doses of steroids. This P01 thus represents a translational
progression of exploration of GVHD biology from basic through translational models to clinical trials that
leverage multiple synergies between projects with the goal to accelerate transformative therapeutic
strategies for GVHD patients.

## Key facts

- **NIH application ID:** 10926901
- **Project number:** 5P01CA039542-35
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** JAMES L. M. FERRARA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,394,938
- **Award type:** 5
- **Project period:** 1997-09-10 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926901

## Citation

> US National Institutes of Health, RePORTER application 10926901, Cellular and Molecular Studies of Bone Marrow Transplant (5P01CA039542-35). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10926901. Licensed CC0.

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