Break It Down For Me, Brother!: ERT and HSCT

So here we go! What is Gracie in for?
I thought you'd never ask! If we follow the study protocol (which is still up in the air, as far as I know), Gracie will have 12 weeks of Enzyme Replacement Therapy (ERT), followed by Hematopoietic Stem Cell Transplant (HSCT, or Cord Blood Transplant), and then, more ERT until the graft catches up.

Umm...Right. Let's start with what's Enzyme Replacement Therapy?
Enzyme replacement therapy is, like we said in the last cheat sheet, the introduction of alpha-l-iuronidase, the enzyme she's missing, into her bloodstream. It gets in there by injection, once a week, and is taken up by all her body cells, except those in her Central Nervous System, which is behind the blood-brain barrier (also discussed in the last cheat sheet, but there's more on it here, too), so the injected enzyme can't get to those cells.

What will that do?
The enzyme in her bloodstream will be taken up into every cell in her body across the capillary walls. These walls have holes in them that let the stuff cells need (like energy molecules, drugs, hormones and the like) get from the blood into the cell. The holes are called "fenestrations" which is a fancy term for "windows". Biologists love their fancy terms for things. :-)
Inside her cells, it will be used to break down the Dermatan Sulfate (the mucopolysaccharide, AKA "GAG" that is collecting in her cells) so that it can be "cleared" or removed from the cell. The broken down pieces of the GAG will go out into the bloodstream and out of her body through the usual channels, like they are supposed to. This therapy will keep her body cells (not brain cells) clear of the offending Dermatan Sulfate temporarily until the HSCT can be done and her cells can start making their own enzyme.

Why can't it get to her brain cells?
Remember the "fenestrations?" The capillaries that go to the brain and other parts of the CNS don't have them. Instead, they have "tight junctions" to hold the vessel-wall cells together, so that only small molecules, or fat-soluble molecules can get across (like oxygen--and alcohol!). The idea is to protect the brain from infections and poisons, but it often protects the brain from medicines, too.

But HSCT can get the enzyme across the blood-brain barrier? How does that work?

The blood-brain barrier keeps out most things that are dissolved in the water part of blood (which is mostly water, anyway) but allows some things that can be dissolved in fat (like alcohol and caffeine) to cross. You can also get molecules across inside a cell membrane. People have been trying to sneak drugs across the blood-brain barrier for a long time, using complicated engineered "transporters" which are supposed to act like cell membranes, but so far haven't worked very reliably. HSCT works on the genius idea that, if you can inject cells from someone else, cells that make the chemical you need, then the blood-brain barrier's really no problem! You can just put the new cell with the enzyme (or other necessary product) into the body and let it go across the BBB as if it belonged there! Furthermore, Hematopoietic Stem Cell Transplant is the implantation of cells that generate more cells (making new blood cells is called "hematopoiesis"--another 50-cent biology word)! That way, the good cells keep getting made without the need to inject any more! Genius!

Boy, that really is genius! And you can infuse it in 15 minutes? So what's the big deal?

Well, every genius idea has to get over a roadblock or two, and there is a substantial roadblock here call the immune system. The immune system is another brilliant idea the body had to protect itself from invaders. When the body detects a cell that doesn't belong to it (like a bacterium, a virus, or somebody else's blood cell) it sends special immune-competent blood cells (macrophages) to go attack it, kill it, eat it, and expel it from the body. It is an extremely effective system that allows people to survive all kinds of germs and bugs that get in, but it's not a very nice way to treat a foreign blood cell that's just trying to help you out. Sadly, the immune system can't tell the difference.

Fortunately, there is a way out of this connundrum. Unfortunately, it involves blowing out and resetting Gracie's immune system. More on this, and what makes HSCT so risky in the next biology cheat sheet.