Navigation Links
Scripps scientists find calcium channel blockers help normalize lysosomal storage disease cells
Date:2/4/2008

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, -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 catheterXusually in a doctor's officeXa 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 -mannosidosis and type IIIA mucopolysaccharidosis. People with -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 levelsXaltering calcium homeostasisXin 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.


'/>"/>

Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

Related medicine news :

1. Scripps Research scientists shed new light on how antibodies fight HIV
2. Scripps Health Treats More Than 160 Fire Victims at Emergency Departments Across San Diego County
3. Scripps research scientists discover chemical triggers for aggression in mice
4. Scripps research scientists find new genetic mutation that halts the development of lupus
5. New prion protein discovered by Canadian scientists may offer insight into mad cow disease
6. Scientists Probe Sepsis Deadly Secrets
7. Scientists puzzled by severe allergic reaction to cancer drug in the middle Southern US
8. Scientists Develop Natural Protection for Stored Foods
9. Scientists detect presence of marburg virus in african fruit bats
10. Scientists Spot Brains Free Will Center
11. Scientists ID Likely Culprit in Popcorn Lung
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/8/2016)... ... February 08, 2016 , ... Brenntag Specialties, Inc.(BSI) , ... Food & Beverage and Dietary Supplement market segments across the ... USA geographies east of the Rocky Mountains since 2012. Consistent performance in ...
(Date:2/8/2016)... ... February 08, 2016 , ... ... LA, celebrates the beginning of a new charity campaign. As part of their ... Special Advocates (CASA). In the belief that children deserve a voice, and in ...
(Date:2/8/2016)... ... 2016 , ... A man who has struggled to quit smoking, a man who has struggled ... to find solutions to his problems – and he did. Now Nabat, a serial entrepreneur ... introduce his breakthrough inventions to the world and better people's lives. His own experience with ...
(Date:2/8/2016)... ... ... If you are feeling that your clothes are a tad snug, the ... Center for Disease Control and Prevention (CDC), 34.9% of U.S. adult women are overweight. ... some of the leading causes of preventable death. February is heart health month ...
(Date:2/8/2016)... Hilton Head Island, SC (PRWEB) , ... February 08, 2016 , ... ... Head and surrounding areas with a vital new community enrichment program, has teamed up ... to local women and children suffering from intimate abuse. To support all those victimized ...
Breaking Medicine News(10 mins):
(Date:2/5/2016)... , Feb. 5, 2016  Syneron Medical Ltd. ... device company, announced today that William Griffing ... America, is scheduled to participate in the Leerink ... on February 11, 2016 in New ... institutional investors to meet with the Mr. Griffing ...
(Date:2/5/2016)... 5, 2016 ... the "Global Musculoskeletal Partnering 2010-2016: Deal ... to their offering. --> ... the "Global Musculoskeletal Partnering 2010-2016: Deal ... to their offering. --> ...
(Date:2/5/2016)... , Feb. 5, 2016  Zimmer Biomet Holdings, ... of the previously announced underwritten secondary offering of 11,027,558 ... stockholders, consisting of affiliates of Blackstone and Goldman Sachs. ... an initial price of $96.45 per share. The selling ... offering.  Neither Zimmer Biomet nor any of its directors, ...
Breaking Medicine Technology: