# Modeling Down Syndrome Neural Phenotypes with Chromosomal Silencing

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $32,224

## Abstract

Project Summary:
 Down syndrome (DS), or trisomy 21, is the leading genetic cause of intellectual disability in children,
with approximately 1 in 700 live births carrying an extra copy of chromosome 21. Compared to less common
single gene disorders, DS pathogenesis is still poorly understood. Treatment for DS would require either
identification of molecular pathways to target with conventional therapies or, potentially, chromosomal therapy
to silence the many possibly disruptive genes on the trisomic chromosome. One window of therapeutic
intervention lies in the Alzheimer’s disease pathology that almost all DS patients suffer from in middle age.
Recently, the extra chromosome has been silenced in an inducible manner by targeted insertion of a transgene
for the XIST gene into human induced pluripotent stem cells (iPSC). XIST normally silences one X
chromosome in females, providing a natural mechanism of dosage compensation. Chromosomal silencing in
DS cells provides a powerful isogenic and isoepigenetic model for studying DS pathology and marks the first
step towards the goal of chromosomal therapy for DS patients. The proposed work will investigate the effect of
silencing the extra chromosome on DS iPSC-derived neuronal cells, investigating both DS and Alzheimer-
specific phenotypes.
 Aim 1: In order to investigate the effect that chromosomal silencing has on DS neural phenotypes in
vitro, iPSCs will be differentiated into neurons using conventional two-dimensional neuronal culturing
techniques and three-dimensional organoids. Cerebral organoids are a recently-developed tool that have been
shown to be a useful model for human brain development, and have been used to study disorders of brain
development. Neurons derived from iPSCs with two and three functional copies of Chr.21 will be compared for
phenotypes that DS neural cells are thought to possess. These include an increased glia:neuron ratio, altered
dendritic spine morphology, and altered mitochondrial morphology. Three-dimensional cultures will be used to
investigate less well-explored pathologies such as alterations in cortical lamination. This aim will also address
the important therapeutic question of whether post-mitotic cells can support chromosomal silencing.
 Aim 2: The same chromosomal silencing system will be used to investigate Alzheimer’s-associated
neuronal phenotypes. These include intra and extracellular amyloid deposition as well as intracellular
hyperphosphylated tau deposition. Due to its relatively late onset compared to general intellectual disability, the
Alzheimer’s disease component of DS is most suitable for therapeutic intervention. Studying the effect of
chromosomal silencing on Alzheimer’s phenotypes provides a strong model for Alzheimer’s pathogenesis while
also bringing this novel strategy one step closer to therapeutics.
 This proposal seeks to utilize a novel chromosomal silencing technique to better model human neural
phenotypes in DS and associated AD.

## Key facts

- **NIH application ID:** 9899750
- **Project number:** 5F30HD086975-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jan Czerminski
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,224
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899750

## Citation

> US National Institutes of Health, RePORTER application 9899750, Modeling Down Syndrome Neural Phenotypes with Chromosomal Silencing (5F30HD086975-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9899750. Licensed CC0.

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