by Kirk, Edwin;
The lysosomal storage disorders manifest in different ways, depending on which enzyme is deficient. Some mainly affect the brain, others the liver and spleen; some affect nerves, or the heart. Hurler syndrome affects most parts of the body. The affected child’s liver and spleen enlarge progressively. The heart valves stiffen and the heart muscle can fail. Cartilage and bone grow abnormally, so that children are very short and can have serious spine and joint problems. The tongue grows larger over time, and facial features become heavier, an appearance that is often (rather unkindly) described as ‘coarse’. Joints stiffen, there can be problems breathing, especially during sleep … and, worst of all, there are progressive effects on the brain. At first, an affected child’s development is normal, but it slows and then stagnates. Finally, as the neurological damage progresses, skills are lost, and, by the time of death, often before the age of ten years, there is profound disability.
This was the grim news I had to give to each child’s parents about their young son.
I also gave them hope, of a sort, and a choice.
Like many genetic conditions, Hurler syndrome is part of a spectrum. With just a little bit of enzyme that works, there can be a less severe picture: the brain might be spared altogether, the first symptoms might start later, and the progression of disease might happen more slowly than in a child with the typical severe form. With just a bit more enzyme again, the picture can be very different indeed. I once met a woman in her 30s who was a little shorter than average, and who told me that she had had severe joint problems — but looking at her, I would never have guessed that she had a variant of Hurler syndrome.1 What’s more, the differences in enzyme function between those who are most severely affected and those with less-severe problems are tiny — one study found that children with the severe form of Hurler syndrome have about a fifth of 1 per cent of normal enzyme activity; those with the in-between form have about a third of 1 per cent; and those with the least severe form, like the woman I met, about 1–2 per cent of normal enzyme activity. It’s very likely that, if you had 3 per cent of normal activity, you would be completely healthy, and virtually certain that you would with 5 per cent.
[1 She had Scheie syndrome, which was once thought to be a separate condition but was later discovered to be effectively a less severe, or attenuated, form of Hurler syndrome. This group of conditions, the mucopolysaccharidoses (try saying that five times quickly) are thus numbered I, II, III, IV, VI, and VII. There’s no V any more.]
This pattern is true for many different conditions that are caused by enzyme deficiencies. The body makes a lot more of most enzymes than it needs. When researchers found this out, they drew the obvious conclusion: we ought to be able to treat people with these conditions, if we could just get a little enzyme back into their bodies.
One of the ways this has been done, and done very successfully, is to manufacture enzyme outside the body and give it to people in the form of regular infusions into a vein. Getting this to work was no simple task. The first condition for which enzyme replacement therapy was developed is called Gaucher syndrome. The idea of treating Gaucher syndrome this way was suggested by Dr Roscoe Brady in the 1960s, and it took until the 1990s before there was a fully-fledged enzyme treatment on the market. Brady and his team spent much of the 1970s extracting tiny amounts of enzyme from placentas, but eventually it became possible to manufacture the enzyme using Chinese hamster ovary cells2 that have been modified to make the human enzyme in large quantities. One of the discoveries that was made along the way was that, to get the enzyme to where it needed to be, a string of sugars attached to the surface of the protein had to finish with one particular sugar, called mannose-6-phosphate — hence the title of this chapter.
[2 I am not making this up.]
Enzyme replacement therapy works well for many storage disorders, up to a point. It’s great for the soft, squishy parts of the body with a good blood supply to deliver the enzyme where it’s needed — the innards, if you will. People with Gaucher disease can have hugely enlarged livers and spleens; the treatment melts those away like ice in the sun. However, for conditions where bones and joints are severely affected, the results tend to be marginal, at best. Worst of all, enzyme can’t get into the brain. For someone with severe Hurler syndrome, giving them enzyme might help with some of the effects of the condition, improving quality of life for a time, but it would not change the long-term outcome.3
[3 For people with the less severe forms of Hurler syndrome, whose brains are not affected, the benefits are clearer.]
There was another option for Ethan and Angelo, a medical roll of the dice. There is a way to get healthy cells into a person’s brain, cells that are capable of producing enzyme that can then be absorbed by the brain cells. The way to do this is far from obvious: you start by poisoning the patient’s bone marrow. Then you replace it, using stem cells from someone else’s marrow. This is bone marrow transplantation,4 and it was developed for treating leukaemia and lymphoma, and, less commonly, some other types of cancer. The concept is simple enough: you have a cancer of the immune system, so you get rid of all of the cells of the immune system completely, and replace them with healthy ones.5 Another application, not surprisingly, is treating disorders of the immune system and other blood conditions. An immune system that doesn’t work properly is replaced with one that will.
[4 More accurately: haematopoietic stem cell transplantation, or HSCT. Haematopoietic stem cells are cells that are capable of making blood cells of all types, and they include cells taken from marrow, but also can be cells taken from the placenta via the umbilical cord after a baby is born (cord blood), or even extracted directly from the blood itself.]
[5 There are other ways this can work. Sometimes, for cancers that don’t involve the bone marrow, the patient’s own marrow is extracted and stored. This allows the use of powerful treatments, such chemotherapy, that would otherwise be fatal because it destroys the bone marrow as a side effect. Once the treatment is over, the patient’s marrow is restored from the backup that has been saved.]
The reason this might work for children with conditions like Hurler syndrome is simple enough: because infection can develop anywhere in the body, white blood cells are needed everywhere. Helpfully, they produce extra enzyme, which other cells can absorb and use. Your brain contains a lot of white blood cells — something like a tenth of all the cells in your brain are a special type of white cell, called microglia. Replace those, and you have a rich supply of enzyme, right where you need it.
There’s a catch. There are several catches. The first is that the treatment is a very big deal. The drugs that are used to kill off the child’s own bone marrow are — not surprisingly — toxic. In part because of this, and in part because of the risks of overwhelming infection while the new immune system establishes itself, there is a substantial risk that the child might die from complications of the bone marrow transplant itself. Those who survive may have lasting side effects from the drugs, or the new immune system may attack their bodies (‘graft versus host disease’). Then, even if the transplant goes perfectly, it takes at least six months for the new white cells to reach high enough levels in the brain to do any good, time in which damage is steadily getting worse. Both boys had early signs that their brains were affected already. The outcomes from a transplant for their brains were uncertain, although it was very likely they would have at least some long-term impairment. And, lastly, this would not be a cure — it would at best change a fatal condition into a chronic one, with gradual worsening of the bone and joint problems in particular.
Faced with a choice like this, what would you do?
In genetics, we make a virtue of non-directive counselling. The idea is that we give people information that empowers them to make their own choices, rather than telling them what to do. Not everyone I see is comfortable with this model — we are used to getting advice from our doctors, after all — and it’s fairl
y common, in a difficult situation, for people to ask me, ‘Yes, but what would you do?’ There are good reasons why this information may not be helpful. The choice that is best for a married medical professional in his 50s, who already has adult children, may not be best for a 19-year-old single mother, or a 44-year-old couple who are facing a possible problem in what may be their only pregnancy ever. So I don’t often answer this question directly; but, of course, I always have an opinion.
Not this time. I have absolutely no idea what I would do in this situation; the choice seems impossible. Accept that my child has a progressive condition that will lead to his death within the next seven or eight years, and focus on giving him as much happiness as possible in his short life? Or take a chance on a treatment that will certainly cause short-term suffering, might kill him outright, might cause serious, lasting side effects, is unlikely to completely save his brain from the effects of the disease, and will leave him with a lifetime of serious, painful bone and joint problems?
Ethan’s parents made one choice, Angelo’s made the other.
Whose parents made the right choice? Both. Neither. I don’t think there is an objective right or wrong here.
Fortunately, dilemmas like this are rare, but it’s not unusual that a treatment for a genetic condition is only partially effective, changing one condition into another, and, especially, changing a life-shortening condition into a long-term disability. We are getting better at it, and there are already many conditions for which there are specific, targeted treatments. Most of these don’t work directly at the level of the gene, but tackle some aspect of the condition’s biology — aiming to restore balance to some system within the cell, or in the body as a whole. Your body can’t process X and it builds up, causing you harm. So we give you a medication that stops your cells from making any X, and perhaps put you on a low-X diet as well. Your body can’t make Y, so we give you supplements of Y. That sort of thing.
There’s a specific group of conditions, called inborn errors of metabolism — mistakes in the way the body’s chemistry works — that particularly benefit from this kind of approach. For some people,6 it can be as simple as taking a regular large dose of a specific vitamin, to kick a sluggish protein into action or prop up a chemical reaction that isn’t quite working properly. By a strange twist, our patients in this group benefit from the existence of the vitamin and supplement industry. Huge numbers of people take large doses of vitamins that they do not need.7 This creates a market (and competition) that results in those vitamins becoming available to the very few people who actually do need to take them, at much lower prices than would otherwise be the case. If you’re someone who has been conned by the industry into taking unnecessary vitamin supplements, you can take some comfort from the knowledge that you aren’t just creating expensive urine. You’re also helping a group of patients with rare conditions. Thank you!
[6 I don’t want to give the impression that all metabolic conditions can be treated this way. Only a very small subset of people with inborn errors of metabolism have conditions that can be effectively reversed by treatment with vitamins, although there are more who benefit to a smaller degree.]
[7 Of course, there are people who do need them. If you have a vitamin deficiency that was diagnosed by an actual doctor, or have some other medical condition that requires vitamin supplements, for goodness sake keep taking them! And if you are a woman who is planning a pregnancy, it’s really important that you take folic acid, because it will reduce the risk of some serious health problems in the baby, and there are some other vitamins that are worth considering. But if you started taking vitamins or other supplements without medical advice, because an advertisement told you it would ‘boost vitality’ or will ‘make you feel better’ or ‘support your immune system’ or something similar … it’s very likely indeed that you would be better off just eating food. Even a moderately well-balanced diet is likely to contain all the vitamins you need. Taking extra won’t help you.]
Cantú syndrome is a condition for which this type of medical balancing act really ought to work, and recently we gave it a go.
Soon after the Dutch-led discovery of the main cause of Cantú syndrome, Kathy Grange made a different type of discovery. Remarkably, on the same campus as the hospital where she worked, there was a scientist, Colin Nichols, who is internationally renowned for his work on potassium channels — the type of protein that is overactive in people with Cantú syndrome. Neither knew of the other’s existence, but, the same day he read the Dutch papers and saw Kathy’s name as a co-author, Colin was knocking on Kathy’s office door. The pair wrote their first paper together the next year: ‘KATP Channels and Cardiovascular Disease: suddenly a syndrome’. Never mind the first five words: the last three tell the story. Colin had been working in pure science, and, out of the blue, he had a brand-new human condition to sink his teeth into. He got to work immediately.
Colin is tall, lean, blue-eyed, enthusiastic. His Northern English accent seems a little out of place in St Louis, Missouri, where he and Kathy work, but he is very much at home there, having worked at the Washington University School of Medicine in St Louis since 1991. The first time I met Colin was in Utrecht, in the Netherlands, at the first meeting of the Cantú Syndrome Interest Group, an international group of scientists and doctors who share the goal of better understanding the condition and learning how to best to treat it. We were there for a symposium and a research clinic.
At a subsequent meeting of the group, in St Louis, Colin and his trainees presented work on mice that had been genetically engineered to have a version of Cantú syndrome. The condition isn’t exactly the same in mice and humans — it’s hard to spot when a mouse has an excess of fur, for instance — but mostly it’s a pretty good match. This means you can do things such as testing possible treatments on the mice, that you might not be quite ready to try on humans. I was particularly impressed by some work on lymph vessels from the mice. People with Cantú syndrome often have a build-up of fluid in their tissues, called lymphoedema. Colin showed us pictures and videos of lymph vessels from Cantú mice, comparing them with ordinary mice. Normally, these tubes collect fluid that has leaked out from the blood into the body’s tissues, and carry it back to the bloodstream. In healthy mice, the muscle in the wall of the tubes pulsed constantly, squeezing rhythmically to force the fluid towards the heart. The Cantú mice were a different story … their lymphatic tubes sat limply, hardly moving at all. It seemed there was an obvious link with the problem of lymphoedema in humans with Cantú syndrome.
That was interesting — but what made us really sit up and pay attention was what happened when Colin’s student treated the mouse tissues with medicine. There’s a group of drugs called sulphonylureas, which work on a slightly different version of the same channel that’s affected by Cantú syndrome. Instead of being found in blood vessels and lymph vessels, this channel is important in the pancreas. Yes, we’re back to the pancreas, and diabetes. The reason that insulin isn’t the only treatment for diabetes is that there are different reasons why people can develop diabetes. If your pancreas completely fails to make insulin, for any of a number of different reasons, then it’s definitely insulin you need. When Banting and his colleagues worked out how to make a safe, reliable supply of insulin, it was this type of diabetes — called insulin-dependent or type 1 diabetes — that they were treating. In its most common form, this is an immune disease. The body’s immune system mistakes the islet cells of the pancreas for a threat and destroys them.
Non-insulin-dependent or type 2 diabetes is a different kettle of fish. It’s an insidious condition in which the body’s cells become resistant to the action of insulin, and the pancreas gradually loses the capacity to make enough insulin to compensate. Because the islet cells keep the ability to release the insulin they do make, treatments that stimulate this release can be effective. It turns out that, if you block the pancreas’s version of the channel that’s
important in Cantú syndrome, extra insulin is released, lowering blood sugar. Sulphonylureas work on this principle: block the channel, allowing the pancreas to release more insulin, and that insulin lowers the patient’s blood sugar. Colin’s student used one of these drugs, called glibenclamide, to inhibit the overactive channels in Cantú mouse lymph vessels. They sprang into life, contracting vigorously as if there were no problem.
If we have a drug that we know works to block some of the effects of Cantú syndrome in mice, and that drug is already registered for use in humans, why not just go ahead and treat all of our Cantú syndrome patients? Well, for a start, we’re worried that it might be dangerous to them. Giving someone who doesn’t have diabetes a blood-sugar-lowering drug might cause them to have low blood sugar, which at worst could be a life-threatening side effect. Also, there is a long history in medicine of people trying treatments that on paper ought to have worked, but which turned out in the real world to be useless, or even dangerous, for unforeseen reasons. Fools rush in where angels fear to treat. If you’re going to try something like this, it has to be done in a careful, controlled way. And if you’re doing that, it would be far better to find a medication that only works on the Cantú channel and leaves the pancreas version alone. Colin is embarking on a search for just such a drug, but such searches can take years and have no guarantee of success.