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Tay-Sachs disease (TSD) and the research can be very complicated to understand. I am not a Phd. or a research expert. I am a mom or dad, relative or friend, fighting to save a child; I need to understand the disease and the research in the simplest terms. I want to tell the story to friends and family and get help!! Let us start with the disease itself.
Tay-Sachs disease is caused by a single broken gene. That mutation causes problems with one of the brains janitors (an enzyme called Hex A). The job of Hex A is to regularly clean out GM2 (this is our villain). GM2 is a big nasty, lazy twisted SOB that likes to hang out in the family room (lysosome) of brain and nerve cells with its feet on the furniture and a lit cigar. In a healthy person the GM2 gathers in the family room and the Hex A makes regular visits to clean up the room. It tells the GM2 to go get a job!! People affected by Tay-Sachs might have no Hex A (a null mutation), they might have a skeleton crew (very little Hex A), and/or they might have mutated Hex A. Mutated Hex A is often still very good at cleaning GM2, but they can not get through doors or up stairs to reach the family room (lysosome). When GM2 accumulates faster than it can be cleaned up, it causes the room to get very crowded and toxic. When the room reaches maximum capacity it is destroyed (it swells up and dies). At the heart of it, Tay-Sachs sufferers have a GM2 accumulation problem.
Researchers have a couple potential approaches to fix this.
Two other important players in treating Tay-Sachs disease are the bodys natural defense system; white blood cells (the bouncers), and the blood brain barrier (BBB), the electric fence around the city. The BBB is one of the most important safety measures for healthy people, we do not want any bad elements (virus or bacteria) getting into our brain. Problem is getting Tay-Sachs treatments across the BBB is a daunting task. Adding Hex A to a body that does not reduce GM2 build up is of no value to a Tay-Sachs sufferer. Treating a neurological condition is much harder than treating other parts of the body. The truth is, we understand very little about how the brain really works. When you consider all the stuff it does; it is far more complicated than any computer. To fix our problem we need to get the good guys through the electric fence and have them go undetected by the bouncers. It is like sneaking into Fort Knox!
Let us talk about some of the research terms you might hear.
Chaperone drugs are useful in people that have mutated Hex A. Chaperone drugs help Hex A get up the steps and into the family room. They slip the bouncer a c-note and tell them the mutation is Jonah Hill. Once in the family room, the mutated on is often superficial and the Hex A can still clean up GM2. The number of mutated Hex A is normally not enough to win the battle, but it can slow the pace of the disease. Chaperone drugs are mutation specific and as a rule, more useful for Late-On Set or Juvenile sufferers. Pyrithiamine is an example of a Chaperone drug that was tested with mixed results.
Inhibitor substrates reduce the production of GM2. If we can create less GM2 the brain will die slower. If we make the GM2 party small enough, we do not need as many Hex A janitors. Zavesca is an example of an Inhibitor. We are currently working on a new inhibitor at Boston College (2016 and 2017). You might ask, why can we not just cut off the production of GM2 all together? I was told that it is because without GM2, other substances would build up even faster and the side effect would be more aggressive than the disease. We are not looking to make this party bigger!!
Enzyme Replacement Therapy (ERT) takes many different forms - gene therapy is a fancy type of ERT. For ERT to work we have to introduce more Hex A AND it has to reduce or eliminate the GM2 build up. One of the biggest obstacles is introducing more Hex A in the brain!! When we add Hex A to the blood stream the Hex A still needs to cross the electric fence (BBB) and then travel the city (brain) looking for the right house (cell) without the bouncers seeing it, finally going to the family room (lysosome) to clean up the party (GM2). If the Hex A has the right papers (DNA) the bouncers will leave it alone, but how do we create Hex A with individual DNA for each person being treated? Another approach is to suppress the immune response (send the bouncers on vacation to Disney), but that can allow other bad things that have been hiding in the weeds access to the city. And they mean it harm!!
Gene Therapy The basic concept is a virus (also called viral vectors or AAV) is used to transport janitors (Hex A) into the city (brain) with portable copy machines so they can create more and more Hex A. It is using the same process that makes you sick. When a virus enters your body it duplicates so quickly that your bouncers cannot keep up. You get sick! In our case they take out the part of the virus that makes you sick and replace it with Hex A. Will the bouncers in the body attack our vectors carrying Hex A? Will the Hex A duplicated by the virus be able to get past the bouncer to enter the house and get into the family room to clean? The Hex A will not have the right papers (DNA), but are their forged papers good enough? It worked in animals; humans are a little more complicated. That is why we do clinical trials, to see if the therapy is safe and then to see if the therapy is effective. Our gene therapy project plans to circumvent the electric fence (BBB) by drilling directly into the brain (city); invasive and risky but a direct route to the problem. In a primate study with a previous version of Hex A, there was quite the battle in the city. An unacceptable development that we have taken the last two years fixing
Stem Cell Treatment is similar to gene therapy except we are trying to use our own stem cells to produce the Hex A. If the Hex A has the right papers (DNA) the bouncers (white blood cells) are likely to leave it alone. That reduces the number of potential complications significantly. Stem Cells have a number of different applications but the research we are sponsoring at UC Davis put stem cells in viral vectors so when the copies are made there should be peace in the city (brain). Everyone should have the proper documentation.
We are always on the look-out for drugs that might breakdown GM2. If we do not have janitors (Hex A), what if we use accountants or electricians or circus performers or one eyed seven foot giants from Rhode Island? Is it possible that other substrates might be able to clean up GM2? One such possibility is Cyclodextrin. It is used to make things like Fabreeze, but it appears to have helped Niemann Pick Type C patients get cholesterol out of the lysosomal storage area. Could it do the same for GM2? We are funding a project at UMass (2016) to see.
You might read about CRISPR or Talens or even Zinc Fingers just to name a few. These are all really cool advancements where scientists are fixing broken genes (DNA). They cut out the broken part and replace it with healthy coding. The challenge for us is a living breathing Tay-Sachs sufferer has billions of copies of that gene, the technology is not ready to fix them all. But lots of money is flowing into this space age science and they might be able to help us sooner than we think.
As we talk about research I think it important we define CURE. Two things need to happen to get our CURE. First we have to halt the progression of Tay-Sachs disease, no more accumulation of GM2. Secondly we have to reverse the damage done before we stopped the disease. Tay-Sachs begins killing brain cells at conception. And a truth all neurologists will tell you; a dead brain cell cannot be brought back to life. So fixing damage is going to be pretty tricky. But the body has billions of brain cells and no one knows for sure what it will do to heal, so anything is possible. For the perspective of our Tay-Sachs community, lots of disease groups want to repair brain damage (Alzheimers, Parkinsons, MS, etc) but only one group cares about excess GM2 accumulations. We need to solve the GM2 problem and hope the big money foundations raising billions of dollars find a way to fix a damaged brain. If we do not do our part there will be nothing left to fix. So we deal with the GM2 problem from every angle.
And finally you hear the term clinical trial, what does that mean? Once a treatment is approved by the FDA (hopefully gene therapy in early 2017) they need to test the safety and then the effectiveness of the treatment. A number of affected people; it could be one, could be six, or could be some number in between. It depends on the FDA requirements and the available pool of qualifying candidates. The qualification will be set through negotiations between the FDA and the research team. Once the qualifications are set, the team will look for and screen candidates. Being a research funder or a Tay-Sachs activist has no bearing on selection; it is purely a scientific exercise. The best way to be on the radar screen of a Researcher, is to have participated in the Natural History Study. The first trial group is given the treatment and then monitored and tested. After six months or a year, a second group (Phase 2) can be selected and treated if everything has proven to be safe. If the clinical trial results are encouraging, than tools like compassionate use can be tried. You could petition the FDA to allow you to get the treatment outside the trial. That is more common with drugs previously shown to be safe in humans that are being tested in a new application.
Here is a video that is slightly more detailed then my explanation for Dummies but some people learn better visually. However we can get the information to you will better arm you to help us fight this horrible disease. In the history of the world no child has survived Tay-Sachs disease, WE AIM TO CHANGE THAT!!
Tay-Sachs Information Video Click Here
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