# Small Molecule Drug Discovery for CLN3 and CLN6 Disease

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $503,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 CLN3 and CLN6 disease are subtypes of a wider family of pediatric neurodegenerative diseases called
the Neuronal Ceroid Lipofuscinoses (NCLs) or Batten Disease. The NCLs affect approximately 6-8 children per
100,000 live births worldwide. Common symptoms of CLN3 and CLN6 disease include vision impairment which
progresses to blindness, seizures which increase in severity, cognitive and motor decline progressing to
dementia, and ultimately premature death. No cure or effective treatment for either CLN3 or CLN6 disease is
known.
 The development of new disease-modifying agents to treat CLN3 and CLN6 disease is an urgent and
unmet medical need. Common phenotypes that are shared between all NCLs include dysfunctional autophagy
leading to accumulation of storage material, reduced expression of the anti-apoptotic protein Bcl-2 and
increased ceramide production leading to apoptotic death of neurons, and dysfunctional mitochondria.
 Autophagy and apoptosis are physiological process that contribute to cellular homeostasis. Dysfunction
of one, or in many cases, both processes, is phenotypic across many neurodegenerative diseases in addition
to the NCLs. While targeting either process individually results in promising pharmacological effect, no small
molecule has been identified that is capable of modulating both synergistically. While a multi-target approach
has been used in cancer treatment for many years, it has only recently begun being applied to
neurodegenerative diseases and has yet to be explored in CLN3 and CLN6 disease.
 Through a structure-based approach, we have identified a library of multi-functional compounds that
fuse autophagy activation activity, anti-apoptotic Bcl-2 induction and decreased ceramide synthesis resulting in
translational activity to protect human induced pluripotent stem cell (iPSC)-derived neurons from externally-
induced and phenotype-induced apoptosis. Moreover, we have shown in our preliminary data that iPSCs
obtained from CLN3 patients and derived to functional neurons recapitulate the aberrant autophagy, apoptosis
and mitochondrial function phenotype of the disease, and that these phenotypes can be rescued by selected
lead compounds. Further, we show proof-of-concept that our lead compounds rescue CLN3 disease
phenotypic behavioral deficits in a transgenic CLN3 mouse model.
 The goal of this application is to optimize our proprietary library of neuroprotective compounds to further
understand their minimum pharmacophore, confer ‘drug-like’ properties, identify and eliminate any potential
toxicity, optimize drug metabolism and pharmacokinetic parameters, further credential their mechanism of
action and demonstrate proof-of-concept protective activity in additional patient iPSC-derived neuron lines and
CLN3 and CLN6 transgenic mice.

## Key facts

- **NIH application ID:** 10873979
- **Project number:** 5R01HD106590-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Paul Trippier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,500
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873979

## Citation

> US National Institutes of Health, RePORTER application 10873979, Small Molecule Drug Discovery for CLN3 and CLN6 Disease (5R01HD106590-04). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10873979. Licensed CC0.

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