# Accelerating remyelination using lanthionine ketimine derivatives

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

The major goal of this project is to identify novel compounds which will accelerate remyelination within the CNS
of patients with Multiple Sclerosis (MS). While many therapies have been developed to treat MS, almost all target
the immune system in efforts to reduce ongoing damage; in contrast relatively few target the regenerative
capacity of myelin producing Oligodendrocytes (OLGs) to restore function. In ongoing studies to characterize
the beneficial effects of Lanthionine Ketimine Ester (LKE), a semi-synthetic amino acid derivative, we found that
LKE not only reduces clinical signs in a mouse model of MS, but also accelerates remyelination following
chemically induced, non-inflammatory demyelination by cuprizone (CPZ). In vitro screening of new LKE
derivatives suggests some are more potent than the parent compound. This raises the main hypothesis that LKE
and new derivatives will increase remyelination and restore functional outcomes. This will be addressed in the
following aims:
Aim 1: Extend our initial studies of LKE benefit using the CPZ model, including optimization of LKE dosage and
duration; and comparisons of LKE following modest (CPZ for 2 weeks) or extensive (CPZ for 5-9 weeks) stages
of demyelination. Assessments will include electron and confocal microscopy of myelin, axons, and Nodes of
Ranvier; analysis of OPC maturation; neuronal damage; and glial inflammation.
Aim 2: Characterize LKE-treatment induced improvement on functional outcomes, including improvement in
nerve conductance by recording compound action potentials across the corpus callosum; and behavioral
analysis to assess motor and balance improvement with rotarod; novel object recognition to assess memory and
anxiety; and y-maze to assess memory.
Aim 3: Complete screening of 4 lead LKE-derivatives to identify those having the highest efficacy (lowest dosage,
more rapid or robust increase) to induce OPC maturation, best metabolic stability, and highest membrane
permeability. The best candidate will be tested in the CPZ model and directly compared to LKE.
Aim 4: Use in vivo and in vitro experiments to explore mechanisms of action of LKE and derivatives. This will
include electrophysiological methods and calcium imaging to examine effects of LKE on CRMP2, and its
interactions with Voltage Gated Ca2+ Channels (VGCCs) in OPCs. Available conditional knockout mice for
CRMP2 will allow testing if CRMP2 in OPCs mediates LKE actions.

## Key facts

- **NIH application ID:** 10708047
- **Project number:** 5I01RX003955-02
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Douglas L. Feinstein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10708047

## Citation

> US National Institutes of Health, RePORTER application 10708047, Accelerating remyelination using lanthionine ketimine derivatives (5I01RX003955-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10708047. Licensed CC0.

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