# Modeling and treating T cell immunodeficiency in CHARGE syndrome by ESC- and iPSC-derived thymic epithelial cells

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2023 · $455,109

## Abstract

Project Summary
CHARGE syndrome is a complex of multiple congenital malformations and occurs in about 1:10,000
births worldwide. T cell Immunodeficiency is common (up to 80%) in CHARGE syndrome and is primarily due
to impairment in thymic development. CHARGE patients with a profound immunodeficiency is one of the
causes of complete DiGeorge syndrome that is due to thymic aplasia. Chromodomain helicase DNA‐binding 7
(CHD7) has been identified as the major causative gene in CHARGE syndrome. Most CHD7 mutations in
CHARGE patients are nonsense, missense, or frameshift, leading to loss-of functions of CHD7. CHD7
knockdown or knockout zebrafish embryos have severely impaired thymus organogenesis; CHD7+/- murine
embryos have thymic hypo/aplasia. However, it is unclear whether the thymic hypo/aplasia in CHD7 deficient
mice and CHARGE patients are due to a defect in the thymic microenvironment. Thymic epithelial cells (TECs)
are the major component of the thymic microenvironment for T cell development. TECs arise from thymic
epithelial progenitors (TEPs) that originate from the definitive endoderm (DE). We have reported that both
mouse and human embryonic stem cells (ESCs) can be selectively induced to differentiate into TEPs in vitro.
When transplanted into mice, ESC-TEPs further develop into TECs, reconstitute the normal thymic
architecture, and support T cell development. We have also shown that CHD7 heterozygous deletion
(CHD7+/-) mouse ESCs (mESCs) have a reduced ability to develop into DE, TEPs and TECs, whereas
homozygous deletion (CHD7-/-) mESCs have more profound defects at each stage of the development. The
recent discovery of reprogramming human somatic cells into induced pluripotent stem cells (hiPSCs) opens a
new window of opportunity by providing an unlimited source of autologous cells for disease pathogenesis
studies and cell-based therapies. We have generated hiPSCs from somatic cells of a CHARGE patient
(CHARGE hiPSCs) and will generate more such hiPSCs. Since CHARGE syndrome is a haploinsufficiency
syndrome in humans, we hypothesize that the heterozygous effects of CHD7 on human DE, TEP and TEC
development from hESCs and hiPSCs are similar in nature to the homozygous effects on matching mouse
cells. We also hypothesize that correction of the CHD7 gene will rescue CHARGE hiPSCs from the defective
DE, TEP and TEC development, leading to normal ability to support T cell development in vivo. Two Specific
Aims are proposed to address the hypotheses: 1) to determine the ability of CHD7+/- hESCs and CHARGE
hiPSCs to develop into DE and TEPs in vitro and TECs in vivo; 2) to determine the ability of CHD7 gene
correction to enable CHARGE hiPSCs to develop into functional TEPs and TECs to support T cell
development. Our proposed studies will not only provide new insights into CHARGE pathogenesis, but also
have potential to lead to novel and powerful approaches to treat T cell immunodeficiency in CHARGE patients.

## Key facts

- **NIH application ID:** 10632290
- **Project number:** 1R01AI175087-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Laijun Lai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $455,109
- **Award type:** 1
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10632290

## Citation

> US National Institutes of Health, RePORTER application 10632290, Modeling and treating T cell immunodeficiency in CHARGE syndrome by ESC- and iPSC-derived thymic epithelial cells (1R01AI175087-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10632290. Licensed CC0.

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