Teachable moment in classrooms:
- cellular basis of life chapter – concept of one gene, one protein
- cellular basis of life chapter – concept of gene mutation leading to protein malfunction
- cellular basis of life chapter – enzymes are proteins
- cellular basis of life chapter – function of lysosome in the cell
- cellular basis of life chapter – protein synthesis and processing
The news item: Recently this report appeared online:
AMT-191 increases enzyme levels in Fabry patients: Early trial data
In a trial, treatment with the experimental gene therapy AMT-191 led to increases in levels of the enzyme whose deficit causes Fabry disease.
The article describes Fabry’s disease as the consequence of a malfunctioning alpha-galactosidase A, where the accumulating fatty substances become toxic for the cells. The article also states that the AMT-191 treatment is an attempt to add back into the body a working alpha-galactosidase A. The article also informs us about some of the side effects of is new treatment.
So, Why Do I Care?? In the USA there are 4000 to 5000 people living with the early onset version of Fabry disease. While this may not look like a large number, but without treatment those people suffer from heart ailments, kidney disease, and neurological symptoms that shorten their life to around 50-60 years. Currently used treatments have variable success rates, so new, effective treatment is welcome news.
Plain English, Please!!! First, let’s talk about the biology of Fabry disease. In a normally working cell the organelles called lysosomes constantly digest unneeded proteins, lipids, carbohydrates. One of those lipids that need to be degraded is called sphingolipid, serving as a stabilizer of the plasma membrane. The digestion is done by several enzymes in a specific sequence. Think about when you have to fix a flat front tire on your bicycle. First, you have to remove the wheel from the frame by loosening the bolts on the wheel axis. Without getting done this first step, you cannot fix the flat. If the bolt is stuck or damaged, then you cannot remove tire, and, thus, you cannot fix the flat. Sphingolipid degradation also has a critical first step, namely the removal of a galactose residue from the molecule. This is done by the alpha-galactosidase enzyme. If the gene that encodes the enzyme has mutations in it, a malfunctioning enzyme is made by the cell, and there will be no degradation of the sphingolipid molecule, and the undegraded sphingolipid will pile up inside the lysosome. The hugely enlarged lysosomes disrupt the functioning of the entire cell. In Fabry’s disease where the alpha-galactosidase is malfunctioning, cells of the kidney, heart and the nervous system are disrupted by the enlarged lysosomes.
Second, let’s talk about conventional treatments. It is intuitive to think that if an enzyme is missing or too slow in the body, then we should add to the body the normal version of the enzyme. Indeed, the so called enzyme replacement therapy works