A very interesting question came up today on the MLD Family Discussion List™ (a private list we run for MLD primary caregivers). I thought it might inspire some thinking so I am sharing my answer here as well:
I have a question and I don’t know if anyone has an answer but I am wondering if anyone knows what truly stops this disease? Is it a normal enzyme level? Will the kids stop declining if the enzyme level stays normal? Are there other things that contribute to the stabilization of MLD??
Your first guess is actually correct – we really don’t know. It will take lots of years of careful study looking at extended clinical trial/Phase III data, combined with more basic science bench work, natural history, and lots of patient & clinic reported progression/outcome data to really understand this disease. And on top of a basic understanding we have hundreds of mutations to study. We’re not planning on shutting down the MLD Foundation anytime soon!
From a practical perspective, the generally accepted consensus is that if the enzyme level in the blood is high enough (remember that “normal” levels vary all over the map and carriers with low blood enzyme levels appear to be metabolically “normal” people) then MLD’s progression will be dramatically slowed or halted. There is truth in this first order basic assumption – but it’s just the start of our understanding.
However (and not to scare you), there are three things to consider as we peel the MLD onion one layer (and there will be more subtleties as we further peel the MLD onion again in the future):
1) The first is that enzyme in the blood is of no value – it needs to be in the nerve cells that need it. Today’s therapies are primarily focused at crossing the CNS (central nervous system) into the brain. We measure enzyme levels in the blood and the CNS because it’s possible – brain biopsies on living people are not good! The state of our ability to get enzyme’s large molecules reliably across the blood brain barrier (BBB) is in its infancy and the results are inconsistent at best. The Milano gene therapy acknowledges this challenge by trying to make sure that whatever gets across the BBB produces 5-10x more enzyme than is typical hoping that the overproducing cells will share enzyme with their neighbors. Think of a gas tank in a car – a full tank shows “F” on the dial, but the engine won’t run if the fuel filter (BBB) is blocking the gas from getting to the engine (the brain).
2) The second thing to consider is once enzyme gets past the BBB will it get to all of the cells that need it? Are some/many of those cells already compromised or unreceptive, does the enzyme (actually it’s a protein) get distributed to all regions of the brain, are the cells fixed so they keep on producing the enzyme or are they waiting for anther infusion like Enzyme Replacement Therapy (ERT) is designed to provide? To continue the car analogy – the car may run if only 3 cylinders (brain regions) get fuel (enzyme) but you really need fuel to get to all of the cylinders (regions of the brain) to have the optimal/desired performance.
3) As mentioned, today’s therapies are primarily targeted at the brain/CNS, but our nervous system has a second component, the Peripheral Nervous System (PNS) that needs to be “fixed” as well. The PNS makes sure the messages from the brain/CNS get to the muscles and systems elsewhere in the body. We have historically seen a lot of transplants where the brain progression is slowed (stopped?) but the motor skills continue to decline (witness the many post-transplant children in wheelchairs). The PNS is slightly different in its makeup than the CNS. It also has a barrier, sometimes called the Blood Nerve Barrier (BNB), which is different from the BBB. The common response when we ask why current research is focused on the CNS and not the PNS is that it makes sense to prioritize the CNS. The challenge is that, to our knowledge, very little work has been done on the PNS barrier aspects of MLD. The car analogy is when the engine is running but the car is in neutral – lots of power under the hood but it is not getting to the wheels (limbs & organs) so the car is not going anywhere.
Also remember that some of these therapies require time to take hold. The transplants need to engraft and the “good” cells take over/replace the bad cells before they can be effective. With ERT the thinking is they need to maintain somewhat consistent levels in the CNS which drives dosages and frequency of infusion. Different issues, progressions and concerns will be at different priorities during the various early and long-term phases of each therapy.
And there are other therapies being developed as well … what if we reduced the amount of sulfatides produced so the little bit of enzyme that many MLD patients have doesn’t have to go as far? This is called substrate reduction therapy (SRT) and hopefully will require a small molecule which, like alcohol, can more easily cross the BBB. In the car analogy we still only get a little bit of gas through the clogged fuel filter – but what if the car was lighter and didn’t require as big an engine – their might be enough fuel getting by to be able to get from point A to point B?
We don’t have to completely understand all of this to make progress and see results in therapies. As I mentioned above, the studies will go on for many more years and hopefully, today’s therapies will be good, tomorrows will be better, and in 5 or 10 years they will be even better as we better understand MLD, the body systems and the therapies of today and the future. But for tomorrows therapies to be optimal, we do have to take the time to learn from every patient, every success, every valiant effort, every failure, and to explore every creative idea – many of which will lead us to increased knowledge even thought they are a practical dead-end.
At our upcoming Board meeting we are going to talk about investing in an independent formal MLD Registry to start to capture this scientific and medical history data in a more accessible scientifically managed database – we want the data to be there for future researchers to study when they have a creative idea. And by investing, I don’t just mean a few dollars, I mean that all of us, all of the MLD patients and their families, will be asked to contribute data as we begin to crowdsource MLD research in ways bigger than just one isolated project after another.