# In utero rescue of cleft palate using maternal administration of folic acid

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $193,750

## Abstract

PROJECT SUMMARY
Craniofacial anomalies accompany a third of all birth defects, with isolated or nonsyndromic clefts of the lip and
palate (CL/P) alone occurring in 1/700 births worldwide. These isolated CL/P have a complex etiology including
both genetic and environmental factors. Isolated cleft palate (CP) alone accounts for 1/1700 cases in the US. In
addition, there are >400 syndromes with CP as a phenotype. Environmental factors such as folate intake and
smoking have been shown to affect maternal environment. While dietary maternal folic acid supplementation
has consistently shown ameliorative effects on neural tube defects, its effect on reducing the occurrence of CL/P
has been variable both in human and in mouse models. Sources of this variability include the dosage and delivery
of folic acid as well as ability to assess the impact of the treatment in mouse models. Several human studies
have speculated that low folic acid dose is not sufficient to prevent CL/P, and that higher doses are more
effective. Our preliminary data indicate that a high daily dose of folic acid given intraperitoneally to pregnant mice
in two short developmental windows is sufficient to rescue CP in utero in Specc1l mouse model of CP. Specc1l
deficiency leads to actin cytoskeletal defects, which results in palatal shelf elevation delay. We have developed
several quantitative 2-D and 3-D analyses to characterize the timing and cellular changes that occur during
palatal shelf growth and elevation. We posit that in utero folic acid supplementation has an ameliorative effect
on the dynamics of palate closure. In contrast to neural tube defects, we argue that rescue of CP requires a
higher daily dose of folic acid administered intraperitoneally but for a short window of time. To our knowledge,
we are the first to use intraperitoneal injection of folic acid to rescue CP. Folic acid has been used extensively in
human studies and has been safe even at relatively high doses. The objective of this proposal is to determine
the minimum possible dose and treatment window for an effective rescue of CP and to study which aspects of
palate closure dynamics are impacted by folic acid supplementation. We will also use sophisticated proteomic
and phosphoproteomic analysis of palatal shelf tissue to determine the molecular consequence of folic acid
treatment. Together, these studies will establish the experimental system and methods to study maternal folic
acid rescue of CP in mice that can be applied to other mouse models. Importantly, these studies will lead to
future therapeutic strategies to reduce the incidence of CL/P in humans.

## Key facts

- **NIH application ID:** 10795114
- **Project number:** 5R21DE032742-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Irfan Saadi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795114

## Citation

> US National Institutes of Health, RePORTER application 10795114, In utero rescue of cleft palate using maternal administration of folic acid (5R21DE032742-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10795114. Licensed CC0.

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