This innovative therapy tries to make use of the mutant Hex A gene. We know the body is actually making a form of Hex A, the problem is the brain cells do not recognize it as Hex A. The brain cells have a kind of quality control department that looks at the Hex A mutants and says – no thanks. The cell does not absorb the Hex A, the waste is not dealt with, brain cells swell up malfunctions and die. What if we could get the brain cells to accept the mutant Hex A?
Chaperone therapy attempts to help the mutant Hex A to make it appear normal. The quality control system of the cell lets the Hex A pass – the chaperone is discarded – and the remaining Hex A is inside the cell breaking down waste. To make it simple – let's say the brain cells quality control system only allow Hex A gene's shaped like the letter "A" inside the cell. The mutant Hex A genes are shaped like B's, C's, or D’s. There are actually over 100 TSD gene mutations.
If a molecule existed that would bond to the B and reshape it into an A – the brain cell would accept it. In chaperone lingo you hear the term "folded." The gene is not shaped right. The shape is the result of lots of different compounds that make up on gene. If you are missing a part, the gene can be misshaped, the gene can break down, or the gene can be unstable.
The science says that if we can give the mutant Hex A some help to get from outside the cell to inside the lysosomal storage area (where the GM2 is), the Hex A will know what to do. The chaperone's job is to help stabilize the mutant gene, pass it through quality control, and then be discarded – to let the Hex A do its thing.
The challenge with a therapy like this is a disease like TSD has roughly 100 different mutant variations – each theoretically need a different kind of chaperone. Additionally, if each mutation needs a different chaperone – will it be cost effective to produce drugs for a limited population? The therapy seems to work better with some enzymes than others – GM2 is proving to be one of the more challenging enzymes.
PYR was previously approved for human use to treat things like malaria. Hope is this inexpensive and very safe drug can increase Hex A levels in Late On-Set and Juvenile patients by 3 to 4%. Those are significant increases and could postpone symptoms or prolong lives by years. This is a very hopeful treatment method.
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