# Epigenetic Silencing of HSA21 in Down Syndrome

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $262,500

## Abstract

Summary
Down syndrome arises from the triplication of a subset of genes on chromosome 21 (HSA21). Individuals with
DS uniformly demonstrate some degree of mental retardation (MR). The MR has been attributed to
impairments in brain development (i.e. neurogenesis) as well as progressive cell death with altered
synaptogenesis (i.e. neurodegeneration). Silencing of one of the three HSA21 chromosomes rescues the DS
phenotype but such a therapeutic approach is limited practically by the efficiency of genomic editing and ability
to specifically target a single HSA21 chromosome. Our preliminary studies show the feasibility of a novel
modified CRISPR approach which greatly enhances the integration of genomic material on HSA21 and we
have also devised a means with which to specifically target a single HSA21 copy. We now propose
experiments to assess the efficiency of these approaches in human DS iPSC lines and following their
differentiation into neural and oligodendrocyte states. We will also address to what extent these interventions
normalize both genetic and epigenetic expression within the DS lines compared to their isogenic counterparts
and whether the DS cells are rescued from a functional perspective (proliferation, cell death, mitochondrial
function and oxidative stress). Overall, if successful, these studies will overcome two fundamental hurdles
needed to treat DS (and other chromosomal abnormalities) from an epigenetic approach and lay the
foundation for potential animal studies.

## Key facts

- **NIH application ID:** 10016836
- **Project number:** 5R21NS115593-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** VOLNEY L SHEEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,500
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016836

## Citation

> US National Institutes of Health, RePORTER application 10016836, Epigenetic Silencing of HSA21 in Down Syndrome (5R21NS115593-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10016836. Licensed CC0.

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