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Improved Disease Model Leads to Potential Therapy for Rare Disorder

Too many potential drugs fail in human clinical trials despite early promise in animal or cell models of disease. Because these models often do not adequately represent human biology, they don't always accurately reflect how patients will react to an experimental compound.

A major area of emphasis at NCATS is the development of model systems for drug testing that more closely resemble human physiology. Such advances can save enormous amounts of time and expense by preventing unsuitable drugs from making their way into human clinical trials.

As an example of this approach, researchers from NCATS and the National Human Genome Research Institute (NHGRI) recently found a way around the roadblock of inadequate models for compound testing. Working collaboratively, these scientists developed a potential treatment for patients with Gaucher disease, a rare, inherited condition marked by enlargement of the liver and spleen, anemia, nose bleeds, easy bruising and bleeding, bone problems, and occasionally neurological problems. The team’s findings were published in the June 11, 2014, issue of Science Translational Medicine.

Gaucher disease is caused by mutations in the gene that codes for an enzyme, glucocerebrosidase (GCase), which helps cells break down waste. In patients with the disorder, defective GCase impairs the functioning of cells called macrophages. Normally, macrophages travel around the body, engulfing dead cells or pathogens such as bacteria. Once inside the macrophage, this cellular debris is shuttled into compartments called lysosomes, where GCase helps degrade it so it can be cleared from the body. In Gaucher disease, however, GCase is misshaped and disposed of before it can get to the lysosomes. As a result, undigested lipids (fatty substances) from dead cells accumulate in the lysosomes of cells in organs such as the liver, spleen, bone marrow and brain.

An intervention commonly used for Gaucher disease is an intravenous infusion that replaces defective GCase with a normal form of the enzyme. However, the treatment costs $200,000 to $400,000 per patient per year, and these individuals must receive the therapy twice a month, often for the rest of their lives.

Ellen Sidransky, M.D., senior investigator in the Medical Genetics Branch of NHGRI and senior author of the paper, has spent the past 25 years studying the biology of Gaucher disease in both patients and animals. "Enzyme replacement has changed the quality of life for many patients," Sidransky said. "Our goal is to find a cheaper and more effective way to treat this disorder."

A Collaboration Is Born

Several years ago, Sidransky suspected that a potential therapy could be a small molecule that would attach to GCase, helping correct how the mutant protein is folded and facilitating its transport toward the lysosome to digest lipid waste. Such compounds are called "chemical chaperones." However, Sidransky needed a way to find the right chaperone. In 2005, she heard about the large-scale molecular screening efforts at what is now the NCATS Chemical Genomics Center (NCGC), part of the NIH Common Fund’s Molecular Libraries Program (MLP). Through MLP, NCATS researchers provide large-scale screening capacity and other resources necessary to identify small molecules that can help scientists study the functions of genes, cells and biochemical pathways.

Sidransky approached NCGC experts with her problem, which became one of the first rare disease projects approved for MLP support. The research team performed a series of screens of NCGC's small molecule library, yielding several promising molecules that enhanced both normal and defective GCase function. When the group tested the top chaperone candidates in skin cells from Gaucher patients, they found that the compounds increased the amount of GCase in the lysosomes — another sign of therapeutic potential. The molecules were particularly promising because they were the first "non-inhibitory" chaperones identified. Up until that point, the group had found only compounds that were inhibitory: at low doses, they acted as chaperones for GCase, but at higher doses, they could inactivate the enzyme, making proper dosing a tricky balancing act. The non-inhibitory chaperones, on the other hand, presented none of these problems.

With these more promising chaperones, it became clear that Gaucher skin cells were imperfect models in which to test the compounds. The skin cells do not accumulate cellular waste like macrophages, the cells primarily affected by the condition. "We wanted to prove that not only does the enzyme function improve, but that it actually degrades the build-up in the lysosome, because that’s what causes the disease process," Sidransky explained. "But we were stuck because we didn’t have a good model for showing that."

Building a Better Model

Recognizing the limitations of skin cells, the NCATS-NHGRI team worked to develop a better model. They wanted to use macrophages created from the blood of Gaucher patients to test the chaperone molecules. But macrophages, especially diseased ones, are notoriously hard to keep alive in a laboratory environment. To create enough of the cells for the large-scale screening studies, the researchers would need to continually draw large amounts of blood from Gaucher patients, a process that was both impractical and burdensome. NHGRI's Elma Aflaki, Ph.D., first author on the paper, found a way around this obstacle by turning patient-derived adult stem cells into macrophages. The stem cells provided the team with a continuous supply from which to create macrophages, eliminating the need to draw blood from patients.

The patient-derived macrophages showed the characteristic low GCase activity seen in patients and — unlike the skin cells — exhibited increased storage of cellular waste in their lysosomes. One of the chemical chaperones identified from the screens reversed these disease features, returning the macrophages to normal functioning. The NCATS-NHGRI team now is working to optimize the molecule for testing in Gaucher patients.

A Potential Treatment for Other Diseases

The team's work not only represents a major advance in the understanding and treatment of Gaucher disease, but it provides a model for scientists to study and explore in other conditions — a major part of the NCATS mission. "We can use what we’ve learned about Gaucher disease to understand neurological disorders that may share underlying molecular defects, and we can tackle them in a similar way," said Juan Marugan, Ph.D., an NCATS staff scientist who, along with colleagues Wei Zheng, Ph.D., and Noel Southall, Ph.D., has worked with Sidransky and her group on the screening efforts.

For example, Sidransky's group has shown that defective GCase is involved in some forms of Parkinson’s disease and related disorders. Parkinson's is a brain disease marked by shaking (tremors) and problems with walking, movement and coordination. Chaperones targeting GCase also could represent potential therapies for this condition.

"What we're learning about this rare disease may revolutionize how we approach common disorders like Parkinson's disease and similar conditions," Sidransky said. "For 25 years, I’ve evaluated and worked with these patients. My hope has always been to come full circle with this research, to develop a treatment to bring back to them." With these advances, she and her team are on their way.


Posted August 2014

Last updated: 08-14-2015
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