Discovery May Increase Treatment Options for Inherited Metabolic Disease Patients
LA JOLLA, CA, February 4, 2008—Scientists at The Scripps Research Institute have discovered that two widely available prescription drugs restore partial cellular folding, trafficking, and function to a variety of mutant enzymes responsible for three distinct lysosomal storage diseases, maladies involving multiple organ system failure.
The study was published online February 5 in the February 2008 edition (Volume 6, Issue 2) of the journal PLoS Biology.
The research team found that the hypertension drugs diltiazem and verapamil increased the overall function of mutant lysosomal enzymes associated with the conditions Gaucher disease, a-mannosidosis, and type IIIA mucopolysaccharidosis in patient-derived cell lines. The drugs worked by reprogramming the innate protein homeostasis machinery of the cell to repair the mutant enzymes. These findings may be especially significant for patients with lysosomal storage diseases affecting the brain, for which there is currently no effective treatment.
"Our study shows that these two widely prescribed calcium channel blockers restore partial enzyme homeostasis in cell lines derived from patients suffering from several lysosomal storage diseases," said team leader Jeffery Kelly, who is Lita Annenberg Hazen Professor of Chemistry, Dean of Graduate and Postgraduate Studies, and member of the Skaggs Institute of Chemical Biology at Scripps Research. "The extent of restoration of mutant enzyme function is thought by many to be sufficient to ameliorate these diseases, opening the door to a new and potentially effective therapy for these patients, especially those suffering from neuropathic lysosomal storage diseases. As with all new therapeutic strategies, safety and efficacy must be demonstrated in humans."
The fact that both diltiazem and verapamil are approved by the Food and Drug Administration for the treatment of cardiovascular disease may pave the way for their use in the treatment of lysosomal storage diseases, once further testing is completed.
Lysosomal storage diseases result from deficient enzyme activity that leads to an accumulation of molecules that the enzymes break down in the lysosomes, organelles or subcellular compartments that normally break down macromolecules utilizing hundreds of degradatory enzymes. In many lysosomal storage diseases, mutations compromise the cellular folding of the lysosomal enzyme, subjecting it to degradation instead of proper folding and trafficking to the lysosome. There are more than 40 known lysosomal storage diseases.
The most prevalent of these is Gaucher disease, which is the most common genetic disorder affecting Jewish people of Eastern European ancestry. Patients with Gaucher disease may bruise easily due to low blood platelets, and they may have enlargement of the liver and spleen. Sometimes they experience fatigue due to anemia. The disease also causes cells in the bone marrow to become engorged with a fatty storage material, which may lead to bone lesions, weakening the skeleton, and sometimes resulting in painful fractures. In some instances, the disease also impairs the function of the lungs or the central nervous system.
Gaucher disease (named after the French dermatologist Phillipe Gaucher, who first described the condition in 1882) is caused by mutations in a person's beta-glucosidase genes, and these defects corrupt his or her beta-glucosidase enzyme. Some of these corrupted enzymes are apparently unstable because they cannot fold properly into their correct three-dimensional structure. The corrupted, mutant enzymes fail to reach the lysosome and to break down fatty glucosylceramides, which then accumulate there.
The current approaches to treating Gaucher disease (and many other lysosomal storage diseases) involve replacing the deficient enzyme and thus breaking down the accumulated substrate. Enzyme replacement therapy is an effective way to restore people to good health, but it has drawbacks. The enzyme has to be infused intravenously or through a surgically implanted catheter—usually in a doctor's office—a process that takes several hours and must be repeated every one or two weeks. Enzyme replacement therapy is also expensive, costing between $100,000 and $750,000 per year per patient.
And this approach to therapy is not effective at treating neurological complications of lysosomal storage diseases because injected enzymes cannot enter the brain. Because diltiazem crosses the blood-brain barrier, the drug could prove to be particularly effective in the treatment of such conditions as neuropathic Gaucher disease, which generally attacks infants and results in severe brain damage.
In addition to acting on neuropathic Gaucher disease, diltiazem and verapamil also partially restored lysosomal enzyme homeostasis in cell lines derived from patients suffering from two other distinct lysosomal storage diseases, namely a-mannosidosis and type IIIA mucopolysaccharidosis. People with a-mannosidosis have an inability to degrade glycoproteins, leading to intellectual disability, hearing loss, frequent infections, and other complications. People with type IIIA mucopolysaccharidosis have a deficiency in one of the enzymes needed to break down heparan sulfate, which leads to progressive central nervous system degeneration. No effective therapy is currently available for either disease.
"We found that these two compounds, diltiazem and verapamil, likely act through a calcium ion mediated increase in the concentration and distribution of cytoplasmic and endoplasmic reticulum chaperones, possibly by activating certain pathways that sense and correct protein malfolding," said Research Associate Ting-Wei Mu, the first author of the study. "Increasing calcium levels—altering calcium homeostasis—in the endoplasmic reticulum appears to be a relatively safe and selective strategy to partially restore mutant lysosomal enzyme homeostasis."
Altering calcium homeostasis in the endoplasmic reticulum does not appear to affect the folding efficiency of other cellular enzymes, the study reveals.
"If we can learn how to successfully manipulate calcium homeostasis, it's possible that these types of drugs might be useful for treating other protein-folding and aggregation diseases as well, like Parkinson's and Alzheimer's," Mu said.
Ernest Beutler, chair of the Department of Molecular and Experimental Medicine at The Scripps Research Institute and an expert on Gaucher disease, is currently developing animal models of neuropathic Gaucher disease that Kelly and his colleagues hope to utilize in collaboration with the Beutler group to further evaluate the utility of diltiazem, verapamil, and their analogs.
The other author of the study, Partial Restoration of Mutant Enzyme Homeostasis in Three Distinct Lysosomal Storage Disease Cell Lines by Altering Calcium Homeostasis, is Douglas M. Fowler, who recently earned his Ph.D. from The Scripps Research Institute.
The study was supported by the National Institutes of Health, the Lita Annenberg Hazen Foundation, and the Skaggs Institute for Chemical Biology.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
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