Weizmann Institute researchers 'hopeful that we can provide better relief' for Gaucher disease

Researchers from the Weizmann Institute of Science and other institutions have made significant strides in designing a stable human acid-b-glucosidase enzyme, hoping to improve therapy for Gaucher disease and mutation classification.

The study, published by FEBS Journal, was led by researchers from the Department of Biomolecular Sciences at the Weizmann Institute, targeting treatment for Gaucher disease (GD), a debilitating inherited metabolic disorder caused by biallelic mutations in the GBA1 gene, leading to the accumulation of glucosylceramide (GlcCer), a simple glycosphingolipid, and resulting in severe symptoms. To address the limitations of enzyme replacement therapy, the team utilized the PROSS stability-design algorithm to create a stable human acid-b-glucosidase (GCase) enzyme with enhanced therapeutic potential, Dr. Anthony H. Futerman, one of the lead researchers, explained.

"Gaucher disease poses significant challenges for patients, and our goal was to find a more effective therapy," Futerman said. "By designing a stable GCase enzyme, we are hopeful that we can provide better relief to patients and improve their quality of life." 

Modern treatment for Gaucher disease involves the use of recombinant human enzymes, such as Cerezyme. However, some patients continue to have neurological symptoms despite the therapy's success in alleviating other manifestations of the disease. The researchers' approach sought to address that issue by enhancing the stability and efficacy of the GCase enzyme. 

"Our approach is a promising step towards developing an alternative to existing enzyme replacement therapy," said Dr. Sarka Pokorna, co-researcher of the study. "By improving the stability and secretion of the enzyme, we aim to provide better treatment outcomes for patients."

The team's research led to the generation of GCase variants with 55 mutations compared to the wild-type human GCase, one of which exhibited improved secretion and thermal stability. Furthermore, this particular variant demonstrated higher enzymatic activity when incorporated into an adeno-associated virus (AAV) vector, resulting in a more significant reduction in the accumulation of lipid substrates in cultured cells, the researchers reported.

"Our findings show that the stability-designed GCase variant holds great promise for more effective enzyme replacement therapy. The increased enzymatic activity observed in the AAV vector opens up new possibilities for treating Gaucher disease and addressing its neurological symptoms," said Dr. Rosalie Lipsh-Sokolik. The study's impact extends beyond Gaucher disease therapy, as the researchers also developed a machine learning-based approach to distinguish between benign and disease-causing GBA1 mutations.

Dr. Rebekka Nielsen, a key contributor to the machine learning-based approach, emphasized the potential applications of their findings

"Our machine learning-based approach could revolutionize mutation classification, not only for Gaucher disease but also for other diseases with genetic mutations," Nielsen said. "This could be a game-changer in understanding risk factors for patients carrying rare mutations."

The study included contributions from institutions such as the J. Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences, the Department of Life Sciences Core Facilities, Lysogene, and the Department of Chemical and Structural Biology at the Weizmann Institute of Science, the report stated.