# ALDH Activation to treat Fanconi Anemia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $482,616

## Abstract

PROJECT SUMMARY
Fanconi anemia (FA) is caused by mutations in one of at least 19 FA complementation (FANC) group genes,
which are required to repair DNA interstrand cross links (ICL). Patients with FA have congenital anomalies,
hematopoietic stem cell (HSC) injury resulting in increased susceptibility to bone marrow failure (severe
aplastic anemia: SAA) and leukemia, increased sensitivity to chemotherapy and radiation, and high risk of
secondary cancers, even if they are successfully treated by HSC transplantation for their aplastic anemia or
leukemia. Because the mutations underlying FA affect every cell in the body, there is currently no cure for FA.
Recent studies have demonstrated that ICL are caused by reactive aldehydes, such as acetaldehyde
(MeCHO). Oxidation by the aldehyde dehydrogenase (ALDH) family of enzymes detoxify aldehydes. In East
Asia, a highly prevalent point mutation in the Aldehyde Dehydrogenase 2 (ALDH2) gene causes a
semidominant loss of function, and decreased ability to oxidize highly reactive MeCHO. Exposure to MeCHO
occurs through generation by endogenous pathways, exogenous ingestion or inhalation, or as the major
product of ethanol (EtOH) metabolism. The ALDH2*2 mutation results in the well-known “Asian flushing
syndrome” marked by a disulfiram-like response to ingestion of small amounts of EtOH. The ALDH2*2
mutation also results in increased susceptibility to cancer, especially esophageal cancer. Thus, the ALDH2 and
FA DNA repair pathways confer two tiers of genome protection from the toxic effects of MeCHO. Humans and
mice doubly mutated for both pathways rapidly develop bone marrow failure due to the loss of HSC. Our
analyses of mice with a knock-in of the human ALDH2*2 mutation at the murine ALDH2 allele show that, even
in a basal environment, (without exposure to EtOH) HSC are 1) progressively lost, 2) at a competitive
disadvantage to normal HSC, and 3) have a gene expression profile typical of a response to interferons, which
are known inhibitors of stem cell self-renewal. Preliminary results also indicate that EtOH exposure causes
significant decline in HSC numbers in wildtype (ALDH2*1/*1) mice. We have developed ALDH activators
(Aldas), small molecules which increase the activity of both ALDH2*1 and ALDH2*2, or re-direct other ALDH
family members, e.g., ALDH3a1, to also oxidize MeCHO. To measure the cellular aldehydic load, we have also
made unique fluorescence based sensors, which can be used in flow cytometric analyses of individual cells,
e.g., HSC. In this grant we will test the hypothesis that Aldas can protect FA HSC from genotoxic injury by
decreasing the load of reactive aldehydes. We will study murine models doubly mutated for FANCD2 and
ALDH2*2 to determine the protective effect of ALDH2 activation, measure the effects of Aldas on aldehydic
load in HSC, and determine whether recruitment of ALDH3a1 to MeCHO metabolism protects HSC. These
pre-clinical studies have the potential to rapidly translate to ...

## Key facts

- **NIH application ID:** 10178078
- **Project number:** 5R01HL141351-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** DARIA MOCHLY-ROSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,616
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178078

## Citation

> US National Institutes of Health, RePORTER application 10178078, ALDH Activation to treat Fanconi Anemia (5R01HL141351-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10178078. Licensed CC0.

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