Small Molecule Therapy

Batten disease, also known as neuronal ceroid lipofuscinosis (NCL), is a rare inherited neurological condition characterized by loss of vision, seizures, and progressive motor and cognitive decline. There is no cure for Batten disease and therapies focus on improving the patients’ symptoms.

Small molecule therapy is one treatment option currently being researched. It is non-invasive, and the aim is to develop medications that can be taken orally. Small molecule therapy can be divided into four categories: pharmacological chaperones, receptor modulators, substrate reduction therapy, and immune modulators.

Pharmacological chaperones

Once a certain protein is produced inside cells, it has to be folded in a specific way to function. Some genetic mutations, such as some of the ones seen in Batten disease, can reduce the ability of the protein they encode for to fold properly. Pharmacological chaperones are molecules that specifically bind to and stabilize proteins, helping them fold properly.

The small size of pharmacological chaperones makes them suitable for delivery by mouth and facilitates their distribution throughout the body, including the brain and spinal cord.

Pharmacological chaperones have not been tested in clinical trials yet, but in-vitro studies with cells derived from patients with a type of Batten disease known as CLN1 disease produced promising results.

Receptor modulators

Nerve cells have receptor proteins on their surface, known as AMPA receptors. These are activated by a neurotransmitter or signaling molecule called glutamate. Nerve cells communicate with each other through electric signals and AMPA receptors are involved in the fast transmission of these signals.

Research has shown mice that do not have a functional CLN3 gene have elevated AMPA receptor activity. This is the same gene that is mutated in juvenile Batten disease. Treating these mice with EGIS-8332, a synthetic molecule that binds to AMPA receptors and inhibits their activity, led to an improvement in the animals’ abilities to control their body movements. This approach has not been tested in human trials.

Substrate reduction therapy

In Batten disease, waste products such as lipofuscins, made of lipids and fats, tend to accumulate inside cells. This is due to defects in the enzymes that normally break down lipofuscins. Substrate reduction therapy aims to remove these fatty deposits.

A small study in nine patients investigated the effectiveness of a medication called Cystagon (cysteamine) in treating infantile Batten disease. Cystagon inhibits the formation of thioesters, which usually also build  up inside the cells of infantile Batten disease patients. However, the results showed that Cystagon treatment did not decrease disease progression.

An open-label Phase 4 clinical trial (NCT00028262) assessed the effect of Cystagon treatment in combination with N-acetylcysteine, also an inhibitor of thioesters’ formation, in treating infantile Batten disease. Even though parents and caregivers reported less irritability and improved alertness, the combination treatment could not prevent disease progression.

Immune modulators

Inflammation in the brain can cause neurodegeneration or nerve cell death, a characteristic feature for Batten disease. During inflammation, the body produces antibodies that normally bind to and neutralize foreign, potentially harmful compounds, such as bacterial proteins. In the blood of juvenile Batten disease patients and CLN3 deficient mice, antibodies against the patient’s own brain proteins (so-called autoantibodies) can be found. One approach to treat Batten disease is to use agents that suppress the immune system (immunosuppressive agents), and potentially inhibit the production of these autoantiboides.

A randomized, placebo-controlled Phase 2 clinical trial (NCT01399047) assessed the safety and tolerability of the immunosuppressive medication CellCept (mycophenolate mofetil) in patients with juvenile Batten disease. The trial was completed in 2015, but results have not been published yet.

Additional information

Batten disease receives little federal funding. The Charlotte and Gwenyth Gray Foundation raises money for a fund to support research into small molecule therapies. The Jasper Against Batten fund raises money specifically for research into CLN2 disease.

Up-to-date information about clinical trials for Batten disease can be found at


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