# Modulation of lysosomal function for the treatment of Batten disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $344,531

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuronal ceroid lipofuscinoses (NCLs or Batten disease) are among the most devastating inherited disorders
of childhood and the most common cause of neurodegeneration in children in the U.S. There is currently no
cure for these disorders, and treatments remain largely supportive. NCLs are characterized by the progressive
intralysosomal accumulation of undegraded cellular material; this accumulation is thought to result from defects
in the autophagy-lysosomal pathway, but could itself contribute to pathogenesis. Our data show that deficiency
of the juvenile Batten disease protein, CLN3, impairs maturation of a subset of lysosomal enzymes and that
trehalose-mediated activation of TFEB, a master regulator of the autophagy-lysosomal pathway, ameliorates
disease burden in a mouse model of juvenile Batten disease (JNCL). We propose to study novel mechanisms
of TFEB activation that could lead to translational applications for JNCL and other neurodegenerative disorders
caused by defects in lysosome-mediated cellular clearance. First, we will test the hypothesis that trehalose-
induced lysosomal enhancement corrects defective maturation of lysosomal enzymes in JNCL mice (Aim 1).
We will test this hypothesis by conducting experiments of protein maturation and by unbiased proteomic
analyses based on the use of a knock-in Lamp1FLAG mouse line we have generated to efficiently isolate
lysosomes from mouse tissues. Second, we will test the hypothesis that reduction or inhibition of Akt, a kinase
inhibitor of TFEB we have identified, will decrease neuropathology of JNCL mice (Aim 2). We will reduce Akt
activity by using two complementary approaches: genetically, by using Akt1-/- mice, and pharmacologically, by
using an Akt drug inhibitor that is currently in clinical development. Third, we will test the hypothesis that
synergistic pharmacological activation of TFEB by modulation of two orthogonal pathways will result in a
greater enhancement of the autophagy-lysosomal system and better reduction of JNCL pathological hallmarks
than either strategy alone (Aim 3). This hypothesis is based on our finding that the non-receptor tyrosine
kinase, Src, is an essential factor for activation of mTORC1, another kinase inhibitor of TFEB. These studies
will pioneer pharmacological activation of TFEB in a model of neurodegenerative disorder. If successful, this
study will provide a powerful paradigm of TFEB activation that could lay the foundation for the clinical treatment
of Batten disease and, potentially, additional neurodegenerative storage disorders caused by impairment of the
autophagy-lysosomal pathway.

## Key facts

- **NIH application ID:** 10247068
- **Project number:** 5R01NS079618-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Marco Sardiello
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,531
- **Award type:** 5
- **Project period:** 2012-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247068

## Citation

> US National Institutes of Health, RePORTER application 10247068, Modulation of lysosomal function for the treatment of Batten disease (5R01NS079618-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247068. Licensed CC0.

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