# Modifiers of CLN3 disease

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $399,600

## Abstract

PROJECT SUMMARY
 Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of disorders that is
collectively the most common cause of childhood onset neurodegeneration in the U.S. and worldwide. Juvenile
NCL, which is estimated to affect approximately 1 in 100,000 live births, is caused by recessive CLN3 mutation
(hence also now referred to as CLN3 disease). Affected children suffer from progressive blindness, seizures,
psychosis, and cognitive and motor failure, and the disease is invariably fatal. CLN3 encodes a novel
transmembrane protein (CLN3, or battenin) that localizes to the endocytic pathway, primarily in
endolysosomes. The CLN3 protein is implicated in various cellular processes, but the primary function remains
incompletely resolved. Given the lack of incomplete knowledge surrounding protein function, limited
therapeutic targets have been identified, and the only therapeutic approaches that have moved into clinical
testing target secondary inflammation or introduce non-mutated CLN3 via gene transfer therapy. Alternative
rational therapeutic targets are badly needed. The research planned in this proposal is focused on identifying
modifiers of CLN3 disease, which has high potential to lead to new targets for therapeutic development. We
will test a candidate disease modifier that is suggested by CLN3 functional studies, and we will perform
unbiased studies utilizing mouse and human cell-based models. In the first aim, we will build from recent
progress on discovery of an early-stage lysosomal Ca2+ defect, testing whether activation of the endolysosomal
Ca2+ channel, TRPML1, significantly modifies CLN3 disease in mice and in human CLN3 patient cells. These
studies will establish key proof-of-concept data, with high potential to lead to a novel treatment for CLN3
disease, also establishing important insight regarding the mechanisms linking CLN3 to TRPML1. Studies to be
carried out in a second aim will build upon the discovery that features of CLN3 disease have a different rate of
progression in different genetic mouse strains. Using genetic approaches, we will test the hypothesis that a
mutation carried in the mitochondrial DNA of FVB/N mice leads to a more rapid disease, and we will perform
further studies to define the role of mitochondrial quality control in CLN3 disease. The candidate gene
modifiers from these studies will also be tested in CLN3 patient derived iPSC models. This research to identify
and validate CLN3 disease modifying factors has high potential to ultimately lead to novel treatments that
would have a meaningful impact on CLN3 disease in the future.

## Key facts

- **NIH application ID:** 10201373
- **Project number:** 1R56NS113891-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Susan Lynn Cotman
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,600
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201373

## Citation

> US National Institutes of Health, RePORTER application 10201373, Modifiers of CLN3 disease (1R56NS113891-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10201373. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*