High Throughput Screening is used to develop medications. It allows a researcher to quickly conduct millions of chemical, genetic or pharmacological tests. Through this process active compounds, antibodies or genes that affect a particular biomolecular pathway can be rapidly identified. The results of these experiments provide starting points for drug design and for understanding the role of a particular biochemical process in the human body. Tens of thousands of compounds are being tested and will be shared with other centers that are testing an additional 20,000 compounds.
Two drug strategies are currently being studied: lower polyglucosans by lowering glycogen synthase or lower polyglucosans by increasing glycogen branching enzyme. Polyglucosans are an abnormal form of glycogen that cannot be broken down and used for energy in the body. These abnormal glycogen molecules accumulate within cells and cause damage.
1) The enzyme glycogen synthase is involved in converting glucose into glycogen. Finding a small molecule medication that safely slows down the enzyme glycogen synthase will provide a treatment for APBD. By slowing further build up of glycogen it is hoped that the body will then be able to clear polyglucosans that have already formed. Thus, stopping the disease would not only be a treatment, but could ultimately be a cure.
2) Drugs are being tested that will lower polyglucosan bodies by increasing glycogen branching enzyme (GBE) activity. GBE is an enzyme that plays a part in converting glucose to glycogen. Small molecules that bind to and stabilize the mutated GBE will be identified in order to correct the deficiency that results in APBD. A “library” of chemical compounds that are already being used to treat other disorders will be screened to find those that stabilize GBE. This should result in decreased levels of polyglucosans, representing a new treatment approach for APBD and a cure.
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Our three research centers are working on High Throughput Screening. Columbia University, Hadassah University Hospital and Toronto University Sick Kids Hospital.
August, 2014 -A short interview with Dr Orhan Akman
1. What kind of drug options will be available from the pharmacological treatment? (pill, liquid, shot?)
As of now the drugs I used are available in liquid form they are taken like a cough syrup.
2. What other glycogen storage diseases will this research help with?
Glycogen storage diseases occurs mainly because of the excessive accumulation of glycogen which is being produced by enzyme called glycogen synthase. The pharmacological agents we are trying are inhibiting this enzyme, it is not 100% inhibition but we hope slowing in the activity will help our body to eliminate the already accumulated glycogen. In our mouse model we have shown that when we stop the synthesis of glycogen liver cells can use the already accumulated glycogen.
3. On the mice study, you said you're waiting to see whether there are "grave" side effects — is that adjective accurate?
May be it is better to use adverse instead of grave....
4. Do you know the specific population that was sampled in Minnesota for the carrier rate percentage? Also, do you have a contact number for the researchers who did that study?
As far as I know they used the Ashkenazi Jewish descended patients hospitalized for other diseases, this must be the reason of high frequency I attached the paper that has more information about their approach and samples you can also see Dr Natowicz's contact information bottom left corner in the first page.
5. Lastly, I'm still having trouble detailing the specific differences between the two different mutations. Here is the graph I have:
"But the potential breakthrough came in New York out of Columbia University, where Akman discovered a second mutation that generates APBD that may explain positive diagnoses that he had expected to be unaffected carriers."
What detail can be added to differentiate between the two to make the distinction more clear?
Please see the PowerPoint figure attached
Second GBE1 Mutation (1)
6. What is the most important aspect of the new APBD registry?
It is very important to establish the natural history of the disease and expecting the milestones of the disease which we will use as a target to improve when we start our clinical trials.
December 5, 2013 - Here is an in depth look at a robotics demonstration performing the high throughput screening process
July 21, 2013 - Dr. Kakhlon's high throughput screening has been delayed due to a problem of cytosolic staining issues, required to appropriately associate the polyglucosan staining with living cells. He hopes to resolve this in the coming weeks and the assay of 20,000 compounds will continue.
July 21, 2013 - Dr Akman has generated two mouse models for APBD one model has already been published in the journal of Human Molecular Genetics, and is available for scientists who want to study polyglucosan body disease. The second mouse model is almost ready for publication currently we are waiting to generate the data which will tell us how polyglucosan bodies affect its life span.
In our mouse models we are testing the efficacy of four compounds we have found them to be useful for decreasing polyglucosans in cells. These compounds were found by high throughput screening (HTS). There are few more candidates and we will study them in the near future.