# Mapping genotype to phenotype in PCD using iPSCs

> **NIH NIH P01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $609,048

## Abstract

SUMMARY: PROJECT 3
There are striking challenges to the diagnosis, care, and treatment of individuals with primary
ciliary dyskinesia (PCD). These hurdles are implicit to the fundamental biology of PCD. Compared
to cystic fibrosis, a monogenic airway disease, PCD is caused by mutations in >50 genes that
encode proteins involved in ciliogenesis and that result in impaired mucociliary clearance. Unlike
CF, where 90% of individuals carry at least one copy of the same variant, the genetic landscape
of PCD is heterogeneous, both in terms of number of genes and variants within those genes. In
CF, we now have highly effective therapies for those 90% of individuals. There are no precision
therapies for PCD, nor do they seem close. A paradigm shift is required to enable the development
of those therapies. In this proposal, we develop methods to generate a panel of PCD airway cells
using induced pluripotent stem cells (iPSCs). We do so using our established methods to
generate a self-renewing source of airway basal cells (iBCs) from iPSCs capable of differentiating
into multiciliated cells (MCCs). We present preliminary data, demonstrating our ability to efficiently
knock out or precisely edit genes in iBCs and phenotype the ciliary defects that result. We test
the hypothesis that this iBC platform can detect the pathogenicity of PCD mutations and predict
the pathogenicity of variants of uncertain significance. To do so we focus on 5 high priority PCD
genes (Aim 1). We take the novel approach of directly inserting VUS (5 per gene) into a gold-
standard iBC line to determine if they lead to defects in cilia ultrastructure and or function (Aim 2).
In aim 3, we address the intriguing question of why mutations in certain genes (CCDC39 and
CCDC40) lead to more severe lung disease. We test the hypothesis that these genes encode for
proteins with broader biological roles and their loss leads to cell intrinsic defects and not simply
loss of cilia function. Finally, in aim 4 we perform proof-of concept experiments to test the
therapeutic potential of iBCs as an autologous, gene-corrected cell-based therapy approach in
xenogeneic transplantation studies in NSG mice.

## Key facts

- **NIH application ID:** 10768967
- **Project number:** 1P01HL170952-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Finn Hawkins
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $609,048
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768967

## Citation

> US National Institutes of Health, RePORTER application 10768967, Mapping genotype to phenotype in PCD using iPSCs (1P01HL170952-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10768967. Licensed CC0.

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