New treatment for Gaucher disease shows promise

Gregory and Deborah Macres of California lost their son, Gregory, in 1997 when he was 4 years old. Little Gregory suffered from a severe form of a rare genetic disorder called Gaucher disease and died after unsuccessful experimental treatment.

Despite their personal loss, the Macres did not give up the search for a cure for the disease, establishing a charitable foundation to support research in several laboratories around the world, including that of Professor Anthony Futerman in the Department of Biomolecular Sciences at Weizmann University. Institute of Science.

Now, after 25 years of research, Weizmann scientists present an innovative genetic treatment that has shown promising results in mice, including significantly increasing lifespan and preserving motor function. The study is published in the journal Gene therapy.

Gaucher disease is caused by an inherited defect in an enzyme that the body uses to break down a fatty substance called glucocerebroside. When this substance is not broken down, it accumulates in the cell’s “recycling bins,” called lysosomes, where molecules that have completed their life cycle are broken down into their component parts, causing damage that can be fatal. .

The disease is relatively more common among Ashkenazi Jews, who typically have the least severe type – Left-Handed Type I – which does not cause brain damage. The other two variants of the disease are much more serious: Gaucher type II causes severe brain damage, with rapid worsening of symptoms and death before the age of 2, while for people with type III, the Fatal brain damage occurs later in childhood and even adulthood. .

Today’s accepted treatment for Gaucher disease involves repeated injections of intact enzymes to reduce the accumulation of glucocerebroside in body tissues. However, this treatment does not cure the disease, nor does it help with more serious types of Gaucher disease that damage the brain.

This is due to the blood-brain barrier, the dense layer of cells that surrounds the brain’s blood vessels and prevents large molecules, such as the injected enzyme, from reaching their target.

As a result, the most seriously affected patients still lack viable treatment. In recent years, several research groups have focused on gene therapy, an innovative treatment in which a normal copy of the defective gene is inserted into cells, using a virus.

But inserting a normal copy of the defective gene does not necessarily compensate for the genetic defect. To try to overcome this problem, researchers in Professor Futerman’s laboratory cooperated with colleagues in Professor Sarel Fleishman’s laboratory, which specializes in using computer models to design and improve enzymes.

Using an advanced algorithm they had created, scientists in Fleishman’s lab designed a version of the gene that would not only contain the correct recipe for the enzyme, but also an improved recipe leading to a particularly active version and stable, capable of compensating genes. defect and fight against the accumulation of glucocerebroside.

Once the gene was genetically modified, scientists led by Dr. Ivan Milenkovic and Dr. Shani Blumenreich of Futerman’s group injected it into the brains of young mice with a disorder that mimics Gaucher type III, a severe and severe form. incurable disease. The researchers monitored the condition of the pups after treatment by measuring their body weight and assessing their motor function.

The scientists were stunned to discover that, like perfectly healthy mice, most of the diseased mice treated with the altered gene gained weight and lived much longer. The puppies also maintained their motor function and balance, with some even reaching a completely normal level.

Mice that were untreated or given the natural version of the gene lost up to 20% of their body weight during the first four months of the experiment, and their motor function deteriorated as that the disease was progressing.

The researchers then sought to understand why the treatment was so effective. They analyzed samples of mouse brains and found that treatment with the modified gene significantly reduced the accumulation of glucocerebroside in the brain, unlike the natural version of the gene.

“We assume that the improved stability of the enzyme allows it to avoid being degraded in the cell: it survives and carries out its vital work,” explains Futerman.

A particularly important finding was that this treatment reduced brain inflammation. In 2015, researchers in Futerman’s lab discovered that a certain inflammatory protein is expressed at high levels in the brains of people with Gaucher types II and III, and that there is a correlation between the level of expression of genes and disease severity.

They then understood that inflammation plays a key role in brain damage and that the gene is a marker of disease progression.

In their new study, they found that the expression level of this marker and two additional inflammatory genes decreased in mice that received the new treatment. These results were confirmed by MRI scans, which showed a reduction in inflammatory markers in the brain.

“For a quarter of a century, the Macres family has followed my research and I have kept them informed of every development. The innovative gene therapy for the version of Gaucher disease that took their son Gregory is a kind of closure for me,” Futerman said.

“We hope to find partners to help us advance this innovative treatment from further experimentation to human clinical trials.” This research is generating a lot of interest beyond Gaucher disease, which is relatively rare, because studies show that this gene also increases the risk of Parkinson’s disease. »