# IDENTIFICATION AND PRECLINICAL EVALUATION OF NOVEL THERAPEUTIC APPROACHES TO DYSKERATOSIS CONGENITA

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $630,648

## Abstract

Project Summary/Abstract
The rare disease dyskeratosis congenita (DC) is caused by genetic deficiencies in the maintenance of
telomeres, which are the structures that protect the ends of chromosomes. Premature telomere shortening
leads to widespread organ pathology, including bone marrow failure, fibrotic scarring of the lungs (pulmonary
fibrosis) and liver (hepatic cirrhosis), and gastrointestinal disorders. Bone marrow transplantation can
successfully address marrow failure, but other pathologies are not treated effectively. In studies funded by
an NIH R21 grant, the principal investigators demonstrated recently that intestinal pathology involves loss of
normal support of stem cell function by an intercellular communication pathway called Wnt, and that drugs
that restore Wnt pathway signaling (including lithium) can ameliorate this pathology. Here we propose to
investigate lung and liver pathology, in particular to determine if Wnt activators are beneficial in these tissues
as was observed in the intestine. We will also broadly investigate other affected pathways that might provide
points of therapeutic intervention. We will use human induced pluripotent stem cells (iPSCs) and genome
editing to generate key lung and liver cells that can be studied in culture, along with telomerase deficient
mouse models, to investigate these mechanisms and test new therapeutic approaches focused on using
existing FDA-approved drugs. The specific aims are:
1. Characterize defects in human DC iPSC-derived cultured type II alveolar epithelial stem cells, and test the
capacity of pharmacologic manipulations aimed reversing the altered pathways to ameliorate these defects.
2. Characterize defects in human DC iPSC-derived cultured hepatocytes and stellate cells, and test the
capacity of pharmacologic manipulations aimed at reversing the altered pathways to ameliorate these defects.
3. Use mouse models to address the efficacy of pharmacologic manipulations to rescue human DC mutant
iPSC-derived tissues in an in vivo context. This will include determination of the minimum serum lithium
concentration that will rescue human tissues transplanted into mice, and tests of lithium and other small
molecules to rescue mouse models of pulmonary fibrosis and cirrhosis driven by telomere dysfunction.

## Key facts

- **NIH application ID:** 9963358
- **Project number:** 5R01HL148821-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** F. Brad Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $630,648
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963358

## Citation

> US National Institutes of Health, RePORTER application 9963358, IDENTIFICATION AND PRECLINICAL EVALUATION OF NOVEL THERAPEUTIC APPROACHES TO DYSKERATOSIS CONGENITA (5R01HL148821-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963358. Licensed CC0.

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