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. May disease Gaucher van Patients with bruise due to low easily trombocytten. and they may haveenlargement 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. Van diseasealso van In some instances. the function of the lungs or the centrale zenuwstelsel impairs the.
Disease (van Gaucher named after the French who van dermatoloogPhillipe Gaucher. first described the condition in 1882) is caused by enzyme van defects corrupt his or her beta-glucosidase van mutations in a person beta-glucosidase genes. and these. 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. Enzymehas to van The be infused or through a implanted catheter ¡ Xusually in a intravenously surgically spreekkamer ¡ Xa process that takes several hours and must be every one or two weeks. repeated 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 Ą-mannosidosis and type IIIA mucopolysaccharidosis. People with Ą-mannosidosis have an inability to degrade glycoproteins, leading to intellectual disability, hearing loss, frequent infections, and other complications. Mucopolysaccharidosis have a deficiency van People with type IIIA in one of the enzymes needed to break down degeneration van het heparan sulfate which leads to progressive centrale zenuwstelsel. No effective therapy is currently available for either disease.
„We found that mediated these two compounds act through a calcium. diltiazem and verapamil. ion van distribution of possibly cytoplasmic and van increase in likely the concentration and reticulumchaperonnen. endoplasmic by het activating certain pathways that sense and correct protein het malfolding.“ said Research Associate ting-Wei Mu. the first study author of the. "Increasing calcium levels¡Xaltering calcium homeostasis¡Xin 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, itis 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.
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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. |
