# A Small Molecule Enzyme Replacement for the Treatment of CLN1

> **NIH NIH R43** · PALM THERAPEUTICS, INC. · 2021 · $467,091

## Abstract

PROJECT SUMMARY
Significance: CLN1 is a devastating neurodegenerative disorder affecting 1 in 100,000 children born worldwide.
This untreatable disease is characterized by dramatic developmental decline, neuromuscular symptoms, vision
loss, and neuronal death. Unfortunately, patients with this disease rarely survive past childhood. CLN1 is the
result of a loss-of-function mutation in the gene PPT1 that encodes for the enzyme palmitoyl-protein thioesterase
1 (PPT1). PPT1 is a lysosomal enzyme responsible for removing S-palmitoyl groups from proteins. When it is
dysfunctional, as is the case with CLN1, lipids and proteins accumulate in cells and have toxic effects in the
central nervous system, heart, and skeletal system. There are currently no approved therapies for CLN1, and
children with this disease experience an average life expectancy of 8-12 years. Objective: To address the
critical unmet need for CLN1 therapeutics, we are developing the first small molecule PPT1 replacement therapy
for systemic treatment of this disease. We have recently engineered a novel class of depalmitoylating molecules
(DPALMs), which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Using this technology,
we aim to develop compounds that can restore PPT1-like thioesterase activity to CLN1 cells. Preliminary Data:
We have identified a set of DPALM lead compounds that effectively depalmitoylate PPT1 substrates and reverse
abnormal protein accumulation in CLN1 patient-derived cells. Furthermore, we found that DPALMs are effective
at non-toxic doses and are well tolerated in vivo. Specific Aims: We will optimize the potency and drug-like
characteristics of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling
studies. In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening
efforts. A modular and robust synthetic strategy will be used to generate new compounds, which will then be
screened for depalmitoylation activity toward PPT1 substrates. In SPECIFIC AIM 2, we will evaluate the efficacy
of optimized DPALMs in CLN1 model cell lines. Compounds will be tested for their ability to reduce the level of
accumulated proteins, reverse abnormal lysosome morphology, and inhibit apoptosis in in vitro disease models.
The proposed studies will enable the development of a highly active DPALM and accelerate the
commercialization of this therapy for the treatment of CLN1.

## Key facts

- **NIH application ID:** 10325648
- **Project number:** 1R43NS122619-01A1
- **Recipient organization:** PALM THERAPEUTICS, INC.
- **Principal Investigator:** Neal Krishna Devaraj
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,091
- **Award type:** 1
- **Project period:** 2021-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10325648

## Citation

> US National Institutes of Health, RePORTER application 10325648, A Small Molecule Enzyme Replacement for the Treatment of CLN1 (1R43NS122619-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10325648. Licensed CC0.

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