The preclinical study of a therapeutic strategy against Lafora disease is promising

A team of scientists has designed and tested on mice an innovative and promising therapeutic strategy for the treatment of Lafora Disease (LD), a fatal form of epilepsy in children. This new type of drug, called antibody-enzyme fusion or AEF, is a first-line treatment for LD and an example of precision medicine that can treat other types of aggregate-based neurological diseases.

LD is hereditary epilepsy and a neurodegenerative disease caused by intracellular carbohydrate aggregates in the brain. LD patients normally develop until adolescence, when seizures begin. Epileptic episodes become more severe and more frequent, followed by a rapid cognitive decline and a vegetative state. LD patients usually die within 10 years of diagnosis.

"LD is devastating for patients and their families, and there is currently no effective treatment," said Dr. Matthew Gentry of the College of Medicine at the University of Kentucky and one of the study's lead scientists . "We are working to define exactly what causes the disease and to develop effective therapies."

It is now understood that LD is caused by aggregates of toxic carbohydrates called Lafora bodies. Structurally, the aggregates resemble plant starch, the main source of carbohydrates in the human diet.

"Amylase is an enzyme that our body secretes naturally in saliva and in the intestines to break down starch in our food," said Gentry. "A study of the 1970s suggested that amylase could also degrade Lafora's bodies.However, we needed a way to introduce amylase into brain cells, where are the bodies of Lafora. "

Gentry Lab has collaborated with Valerion Therapeutics, a clinical-stage biotechnology company with a new antibody-based delivery platform that can carry active biotherapeutic agents in cells.

"We have fused human amylase to our proprietary antibody fragment for intracellular delivery of the enzyme into mouse cells genetically engineered to develop LD," said Dr. Dustin Armstrong, scientific director of Valerion.

This antibody-amylase fusion, called VAL-0417, virtually eliminated the Lafora bodies in the brain of LD mice and other tissues.

"A continuous infusion of VAL-0417 for seven days directly into the brain restored normal brain metabolism in LD mice, suggesting that VAL-0417 could reverse the disease in humans," said Gentry. "It's been almost 15 years since I've been working on defining the basic mechanisms of LD and it's really amazing to see this science translated into a therapeutic potential."

Epilepsy is a heterogeneous disease with multiple genetic, environmental and sporadic causes that affects 50 million people worldwide. One-third of these patients have drug-resistant convulsions, which demonstrates an urgent need for personalized treatment strategies.

Dr. Kathryn Brewer, also from the UK College of Medicine and co-investigator of the study, pointed out that the results of the study had potential therapeutic applications going beyond this extremely rare disease.

"Lafora disease belongs to a family of human diseases called glycogen storage diseases," she said. "GSDs are caused by gene mutations that lead to poor regulation of glycogen and pathogenic consequences in various tissues.Vererion technology is a promising pharmaceutical platform to treat a range of GSDs."

The study was published in the July 25 edition of Cell metabolism.