# Down Syndrome: a potential treatment XISTs

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $1,693,316

## 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. With prior funding from NIH INCLUDE, we have developed
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 by SNP based PAM
targeting with gRNA. Feasibility has been shown in culture model systems. We now propose experiments to
assess the efficiency of these approaches in the TcMAC1 mouse model of DS. The TcMAC21 mouse contains
93% of HSA21q protein coding genes that are expressed and regulatable. Overall, if successful, these studies
would show the potential ability to reverse, at least partially, the DS neurological phenotype.
The funded proposal is the necessary next step to ascertain whether the efficiency of silencing by XIST of a
third HSA21 copy in vivo would translate into an observable clinical effect.

## Key facts

- **NIH application ID:** 10525816
- **Project number:** 1R01HD109794-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** VOLNEY L SHEEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,693,316
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525816

## Citation

> US National Institutes of Health, RePORTER application 10525816, Down Syndrome: a potential treatment XISTs (1R01HD109794-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10525816. Licensed CC0.

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