Refining the recipe for gene therapy

Prof. Anthony Futerman from the Department of Biomolecular Sciences has been studying Gaucher disease for over 25 years. In a new study published in Gene Therapy, he and his colleagues present an innovative treatment that has produced promising results, dramatically increasing the lifespan of affected mice and preserving their motor function.

Gaucher disease is caused by an inherited defect in an enzyme necessary for breaking down a fatty substance called glucocerebroside. When this substance is not broken down, it accumulates in cells’ “recycling bins,” or lysosomes, eventually causing potentially fatal cell damage. The disease is more common among Ashkenazi Jews, primarily in its least severe form―Gaucher Type I―which does not lead to brain damage. However, the two other variants of the disease are much graver: Gaucher Type II leads to fatal brain damage within the first two years of life, while in Type III, the fatal brain damage manifests later in childhood or even in adulthood.

The current treatment for Gaucher disease is repeated injections of undamaged enzyme to reduce the accumulation of glucocerebroside in body tissues. This treatment, however, does not cure the disease, nor does it help in the more severe types of Gaucher disease that damage the brain because the injected enzyme cannot cross the blood-brain barrier―leaving more severely affected patients without viable treatment options. In recent years, several research groups have focused on gene therapy, an innovative treatment in which a virus inserts a normal copy of the defective gene into cells.

Nevertheless, inserting a normal copy of the defective gene does not necessarily compensate for the genetic defect. Futerman’s team, collaborating with the lab of Prof. Sarel Fleishman, took a different approach: using cutting-edge computer modeling, the Fleishman lab applied an algorithm to design a new version of the gene—an enhanced “recipe” that is more stable and effective at breaking down glucocerebroside, compensating for the genetic defect.

Dr. Ivan Milenkovic and Dr. Shani Blumenreich, from the Futerman group, injected the gene into the brains of young mice with a disorder that mimics Gaucher Type III, and the results were astonishing: most mice treated with the engineered gene gained weight and maintained motor function and equilibrium—some even achieved a totally normal level. The mice also live significantly longer lives. Prof. Futerman hypothesizes that the engineered version of the gene outperformed the natural version thanks to its enhanced stability, which enabled it to evade digestion in the cell―it survives and does its vital job.

One key finding was that this treatment reduced brain inflammation. The Futerman lab previously showed that people with Gaucher types II and III have high levels of an inflammatory protein in their brains, which correlates with disease severity. In their new study, the researchers found that the treated mice showed reduced expression of an inflammatory marker and two other inflammatory genes,

Prof. Futerman is eager to expand his work beyond Gaucher disease, which is rare, because studies have shown that the defective gene also increases the risk for Parkinson’s disease.

Profs. Futerman (left) and Fleishman.

Prof. Anthony Futerman is the incumbent of the Joseph Meyerhoff Professorial Chair of Biochemistry.

Prof. Sarel Fleishman is supported by the Artificial Intelligence and Smart Materials Research Fund, in Memory of Dr. Uriel Arnon; the Nancy and Stephen Grand Research Center for Sensors and Security; and the Dr. Barry Sherman Institute for Medicinal Chemistry.