Alglucerase injection (Ceredase®) – Gaucher disease

Physician-scientist Roscoe O. Brady (1923-2016) was an intramural investigator at NINDS whose decades-long research on lysosomal storage disorders led to the first enzyme replacement therapy (ERT) for Type 1 Gaucher disease.

Tracking down a missing enzyme

Gaucher disease was first described in 1882, by budding French physician Phillipe Gaucher in his medical dissertation¹. Over fifty years later in 1934, French chemist Henriette Aghion determined that a fatty molecule called glucocerebroside was the substance building up inside cells and causing enlarged spleens and livers in patients². While this was a critical advance, the reason for the buildup remained unknown.

By the mid-1950s, physician-scientist Roscoe Brady had turned his attention to Gaucher disease in his laboratory at NINDS. After ruling out other explanations, he hypothesized that a defect in breaking down glucocerebroside was responsible for the disease. He teamed up with chemist David Shapiro from the Weizmann Institute in Israel to make glucocerebroside labeled with radioactive carbon, which they used to trace the molecule’s fate in cells from Gaucher patients and healthy controls. Through these experiments, Brady and his colleagues identified the enzyme glucocerebrosidase that cleaves glucocerebroside³ and showed that Gaucher disease results from deficient glucocerebrosidase activity^{4, 5}, a finding independently confirmed by scientists in the UK⁶. This discovery had early implications for patients, as Brady and his colleagues soon developed a diagnostic test for Type I Gaucher disease⁷, as well as a prenatal test for Type 2 Gaucher disease⁸.

Knowing the cause of Gaucher disease also prompted Brady to suggest treatment through enzyme replacement therapy (ERT)⁹, an idea proposed as a general concept just two years earlier by Belgian scientist Christian deDuve¹⁰, who would later win the Nobel Prize in Physiology or Medicine for his discovery of the lysosome and efforts to characterize lysosomal enzymes¹¹. In 1968, a study by Brady’s team and an extramural colleague determined that glucocerebrosidase is a lysosomal enzyme¹², placing Gaucher disease among other conditions just being recognized as lysosomal storage disorders at the time.

Pioneering enzyme replacement therapy

As a first step toward ERT for Gaucher disease, Brady’s team worked to isolate and purify glucocerebrosidase for initial tests in patients, and with support from the National Lipid Diseases Foundation (NLDF), they eventually developed a method to obtain small amounts of the enzyme from human placenta¹³. They delivered the enzyme intravenously to two patients with Gaucher disease and reported in 1974, that as hoped, the intervention reduced glucocerebroside accumulation in the patients’ livers¹⁴. These results represented important proof of principle for ERT, but Brady and his colleagues knew they would need much more enzyme for further tests than they could obtain using their current method.

After several more years, Brady’s team devised a new protocol to purify the enzyme from placenta in larger quantities¹⁵, but to their disappointment, tests of the enzyme in patients produced inconsistent results¹⁶. In Gaucher disease, glucocerebroside accumulates in cells called macrophages, a type of white blood cell. But back in the lab, Brady’s team and colleagues at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) found that the enzyme they were testing was not getting into these cells as efficiently as needed¹⁷. Based on growing understanding of the structure and transport of lysosomal enzymes¹⁸, they developed a way to modify certain molecular tags on glucocerebrosidase to improve its uptake into macrophages¹⁹.

In 1990, Brady and his team reported improvement across multiple clinical measures in a single child treated with the modified enzyme²⁰. Concomitantly, the young biotechnology company Genzyme (now part of Genzyme Sanofi) had entered the scene. They worked to adapt Brady’s purification and modification procedures for commercial production of the enzyme and collaborated with NIH to conduct a subsequent trial in twelve individuals with moderate to severe Type 1 Gaucher disease. All participants in the trial showed dramatic improvement²¹, and in 1991, the FDA approved alglucerase (Ceredase®), an enzyme derived from human placenta, to treat Type 1 Gaucher disease²². The approval marked the first successful ERT for a lysosomal storage disorder.

Biotechnology and genetics research drive further advances

The development of Ceredase® was a remarkable feat, but Genzyme already understood that supply of the enzyme from human placenta would eventually be inadequate. Indeed, 20,000 placentas were required to purify enough enzyme to treat just one patient for one year. By this time, recombinant DNA technology had made it possible to obtain biological products through cell culture expression systems with higher efficiency than purification from tissue sources. In 1985, NINDS intramural investigator Edward Ginns and colleagues²³, and separately, researchers funded by the National Cancer Institute (NCI)²⁴, cloned and sequenced the human gene for glucocerebrosidase (GBA), paving the way for Genzyme to develop a recombinant form. The recombinant product Cerezyme®, was approved by the FDA²⁵ in 1994, and shown to be as effective for the treatment of Type 1 Gaucher disease as placenta-derived Ceredase® . Today, Ceredase® is no longer produced²⁶, but two additional forms of recombinant glucocerebrosidase have expanded treatment options for Type 1 Gaucher disease: velaglucerase alfa (VPRIV®, Shire) approved in 2010, and taliglucerase alfa (Elelyso®, Pfizer) approved in 2012.

Brady’s work with Gaucher disease served as a model for studying other lysosomal storage disorders. Brady helped identify the genetic causes of Niemann-Pick, Tay-Sachs, and Fabry diseases, and aided the development of ERTs for these previously untreatable disorders as well. Brady’s efforts also had lasting impact by spurring the early growth of the U.S. biotechnology industry. In recognition of his outstanding contributions, President George W. Bush awarded Brady the 2007 National Medal of Technology and Innovation, the nation’s highest honor for technological achievement^{27, 28}.

Current research on Gaucher disease and other lysosomal storage disorders is building on the foundations laid by Brady, his NIH colleagues, and others. Although ERT is effective for Type 1 Gaucher disease, it does not address neurologic features of Types 2 and 3 Gaucher disease because current glucocerebrosidase formulations do not cross the blood brain barrier and are not readily taken up by neurons, even if delivered directly to the brain. Researchers therefore hope to develop new ways to target the therapy to the brain and other less accessible tissues. Investigators are also pursuing gene therapies for Gaucher disease and other lysosomal storage disorders, which if successful, would allow patients to produce missing enzymes on their own, without the need for chronic enzyme replacement. Additional efforts focus on small molecule drugs to improve the function of mutant glucocerebrosidase and on therapies to limit the production of glucocerebroside, the latter of which are already available for type 1 Gaucher disease.

Additional Information

Passing of a Great NINDS Physician-Scientist

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