# Defining and treating peripheral nervous system dysfunction in Cln1 disease

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $196,875

## Abstract

Abstract:
CLN1 disease or Infantile Neuronal Ceroid Lipofuscinosis (INCL or Infantile Batten disease) is one of the
earliest onset and most rapidly progressing forms of neuronal ceroid lipofuscinosis (NCL or Batten disease).
CLN1 disease is caused by deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1), and
has a devastating impact upon the central nervous system (CNS). Symptoms start within the first year of life
and progress rapidly. CLN1 disease is always fatal, and there is no effective therapy. While the
catastrophic effects of PPT1 deficiency upon the CNS are well appreciated, relatively little is formally known
about disease phenotypes outside the brain and spinal cord. In addition to a rapid decline in motor function
leading to immobility, children with CLN1 disease display diverse sensory abnormalities including altered pain
thresholds and hyperexcitability to touch. Our preliminary data from CLN1 disease mice suggest these
phenotypes are due to a pronounced impact of CLN1 disease upon both motor and sensory components
of the peripheral nervous system (PNS) that have been previously overlooked. These include loss of
peripheral axons, denervation of the neuromuscular junction, loss of non-myelinating terminal Schwann cells
and compromised compound muscle action potentials, altered thresholds to mechanical stimuli, loss of dorsal
root ganglia neurons and an upregulation of pain-associated neuropeptides in the dorsal horn of the spinal
cord. The contribution of such PNS phenotypes to CLN1 disease outcome is poorly understood, and CNS-
directed therapies are unlikely to completely treat these PNS manifestations of this disease, which may worsen
over time. Now we will more thoroughly characterize the extent and nature of PNS disease before testing a
gene therapy strategy capable of treating both CNS and PNS defects. We have already demonstrated that
neonatal CNS delivery of an AAV2/9 vector expressing PPT1 remarkably improves brain and spinal cord
function in CLN1 disease mice. We will now test whether combining CNS-targeted and systemic delivery of
AAV2/9-PPT1 will provide better treatment outcomes compared to treating the CNS alone with this vector. We
will achieve these goals with the following specific aims.
Specific Aim 1: To determine the structural and functional integrity of the peripheral nervous system in
CLN1 disease mice.
Specific Aim 2: To treat peripheral nervous system disease with AAV-mediated gene therapy.
Together these studies will provide detailed information about how PPT1 deficiency impacts PNS structure and
function in CLN1 disease mice. Determining the efficacy of gene therapy to treat these underappreciated
consequences of PPT1-deficiency outside the brain, will allow us to refine treatment strategies to improve
quality of life and provide clinically relevant disease outcomes for children with CLN1 disease.

## Key facts

- **NIH application ID:** 10428174
- **Project number:** 1R21NS126907-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JONATHAN D COOPER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428174

## Citation

> US National Institutes of Health, RePORTER application 10428174, Defining and treating peripheral nervous system dysfunction in Cln1 disease (1R21NS126907-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10428174. Licensed CC0.

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