Charting the paths to enzyme replacement therapies for lysosomal storage disorders

Charting the paths to enzyme replacement therapies for lysosomal storage disorders

At the end of January, we launched a new feature on our website that shows how NINDS and the research we support contribute to the discovery and development of treatments for neurological disorders. This month, we are adding two additional narratives to the site, both on enzyme replacement therapies for lysosomal storage disorders.

Lysosomes are compartments inside cells that break down cellular debris into components that can be reused or discarded. People with lysosomal storage disorders lack one or more key lysosomal enzymes. As a result, certain waste products accumulate in cells, leading to a variety of symptoms and often affecting neurological function. Starting with the first enzyme replacement therapy (ERT) ever approved, we highlight how NINDS intramural scientist Roscoe Brady worked for over 20 years to bring the treatment he conceived for Gaucher disease to reality. Brady, who passed away in 2016, was awarded the National Medal of Technology and Innovation for his contributions, the nation’s highest honor for achievement in science and technology. Next, we describe the more recent development of brain-targeted ERT for CLN2 disease, a form of Batten disease. Both narratives illustrate how remarkable advances can emerge from the ideas and persistence of individual scientists, inspired and aided by the patient communities they seek to help.

These stories are also a reminder that science continues to build on itself, in anticipated and unanticipated directions. The success of ERT for Gaucher disease led to ERTs for other lysosomal storage disorders, with CLN2 disease as the newest addition. Meanwhile, mapping the gene (called GBA) for the missing enzyme glucocerebrosidase in Gaucher disease led to other important advances. In 1987, NINDS intramural investigator Edward Ginns and colleagues identified the first of 300 or more currently known disease-causing mutations in GBA, and they were among the first to try treating Gaucher disease with gene therapy, which would allow patients to produce functional enzyme on their own without the need for chronic ERT. While early attempts were unsuccessful, gene therapy research has progressed as a field, and investigators supported by NIH and others continue to pursue its application in Gaucher and CLN2 diseases, as well as many other disorders.

In an exciting and unexpected twist, recent studies of Gaucher disease have led to new insights for understanding and treating Parkinson’s disease. In 2003, Ellen Sidransky at the National Human Genome Research Institute noted that people with Gaucher disease are more likely than expected to develop Parkinson’s disease. She and other NIH intramural scientists went on to show that GBA mutations increase the risk for Parkinson’s disease, whether or not carriers have Gaucher disease, a conclusion that was confirmed in a collaborative study of over 5000 Parkinson’s disease patients. Today, GBA mutations rank among the most common known genetic associations with Parkinson’s disease. Moreover, growing evidence points to a role for glucocerebrosidase in Parkinson’s disease mechanisms even in people without GBA mutations. Potential therapies based on this understanding are currently in development, including some already in clinical trials.

The connection between Parkinson’s disease and Gaucher disease may not be unique, as genes for other lysosomal storage disorders have also been associated with Parkinson’s disease, and more broadly, impaired lysosomal function occurs across neurodegenerative disorders. Indeed, research on rare diseases often yields insights into mechanisms involved in other disorders. Finding these connections and following the opportunities they create will move us closer to more successful therapies.


Related links:

NINDS Contributions to Approved Therapies

Passing of a Great NINDS Physician-Scientist

NIH Office History website exhibit on Dr. Brady and Gaucher disease

Batten disease may benefit from gene therapy

Study Conclusively Ties Rare Disease Gene to Parkinson's

Thursday, June 21, 2018