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

Award Number: R01AI175087
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $412,376 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	TOLLAND	USA	Allergy and Infectious Diseases Research	000	2	1/10/2024	NON-COMPETING CONTINUATION	$412,376
														Subtotal = $412,376

Issue Date FY: 2023 ( Subtotal = $455,109 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	TOLLAND	USA	Allergy and Infectious Diseases Research	000	1	1/31/2023	NEW	$455,109
														Subtotal = $455,109

Grand Total All Awards = $867,485

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

Award Number: R01AI175087

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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