by Kirk, Edwin;
The one situation in which you might experiment with an untried treatment like this is one in which it seems like you have no other options.
One day in late 2017, I was called by a geneticist called Alan Ma. Alan had been asked to see a baby who had been in intensive care since his birth, several weeks before. Born prematurely, Harry weighed more than expected for a baby who had only made it to 32 weeks of pregnancy. He had a patent ductus arteriosus that had needed surgery. He had a lot of hair, including hair on his forehead that merged with his eyebrows. Alan sent me some photographs, saying, ‘It looks like this boy has Cantú syndrome — what do you think?’
Alan also said that Harry had severe lung disease, and, despite all the usual treatments, he was not getting better. Worryingly, there was a report in the medical literature of an infant with Cantú syndrome who had died from similar lung disease.
It seemed that now might be the time to try glibenclamide in a human with Cantú syndrome.
Harry was in an intensive care unit, so that changes in his blood sugar, or any other — unexpected — responses to treatment could be closely monitored. The balance between risks and possible benefits seemed to favour treating. We discussed the situation with the international group, who agreed, and Alan arranged for me to meet Harry and his parents, so that I could speak with them about the idea.
Before we could try an experimental treatment on a sick baby, we had to be absolutely certain of the diagnosis. The quickest way to do this, it turned out, was to do exome sequencing. We would read the sequence of all 23,000 of Harry’s genes, even though we were interested in just two: ABCC9 and its partner KCNJ8. This was one of the first times an Australian lab had done this as an urgent test, and it was a complete success — in just four days, we had our answer. Harry had a change in his ABCC9 gene that had been seen before in other Cantú children. We had our confirmation. Even better, Colin had already studied this particular change and showed that it could respond to glibenclamide in the laboratory. Alan applied to the hospital for permission to use the drug, and, cautiously, starting with a tiny dose, began the treatment.
Around the world, the Cantú community — who had agreed this was the right thing to do — held their collective breaths.
I wish I could tell you that the treatment was a miracle cure. The truth is more complex than that. Slowly, Alan increased the dose of the drug. Slowly, Harry’s condition improved. His face and limbs had been swollen with fluid; the fluid cleared. His lungs gradually got better, too — not all at once, and not without setbacks, but eventually he was able to leave the intensive care unit, and finally he was discharged from hospital altogether. His blood sugar did drop a couple of times, but only mildly. We saw no evidence that the drug was harming him otherwise. Two years down the track, Harry’s lungs were still working fine, and he was still taking the glibenclamide.
Did the treatment save Harry? In the paper we wrote describing all of this, we said, ‘it is tempting to conclude that glibenclamide was of benefit to our patient’, which I think strikes the right note of caution. I would love to think that the treatment helped with his recovery — and that’s a problem. If you want a particular outcome, it is all too easy to fool yourself about what happened. Perhaps Harry was going to get better anyway. Maybe the drug did nothing, or actually made things slightly worse. Study a single child, and it’s almost impossible to know for certain whether you have made a difference.
You might argue that it hardly matters. We treated a sick baby, his condition improved … who cares whether the treatment made him better or he recovered on his own? The problem is that there is a particular trap that lies in wait for those who treat rare diseases. Once you use a treatment in someone who has a very rare condition, that treatment might become standard practice, even if it doesn’t actually help. It then becomes next to impossible to do the studies that might show whether it really does work or not, because nobody would be willing to have their child (or themselves) potentially given a placebo instead of the treatment that ‘everybody knows you use for (condition X)’.
That’s not to say we should never try drugs on a one-off basis, as we did here. There are things we can learn from an n=1 study (a study of a single patient). We learned that the drug was not obviously harmful to Harry, within a particular range of doses. We gained some initial observations of the problems that might be helped by the treatment (the excess fluid, the problem with his lungs) and also of others that seemed not to be changed at all (the excess hair, for instance). In the ideal world, we would do a controlled study, in which patients with Cantú syndrome were treated, randomly, with either drug or a placebo, with both the doctors and the patients (and their families) unaware of which the patients were receiving. This is the randomised controlled trial, which is the gold standard when you’re trying to find out if a new treatment is effective. But when the numbers are tiny and the need is great, sometimes we have to do the best we can for the child in our care; study the outcome; and report it in the medical literature so that others can learn from our experience, and add to it with theirs.
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The past few years have seen an explosion of new treatments for genetic conditions, many of which are already at a very advanced stage of readiness, or have even reached the market as drugs that can be prescribed. I recently saw a French doctor, Guillaume Canaud, receive a standing ovation at a European conference,8 after giving a talk about treatment for a complex condition in which there is massive overgrowth of limbs and tissues. Canaud had found out that the drug was being developed as a treatment for cancer, because, in some cancers, the gene involved in the syndrome (PIK3CA) is overactive and contributes to the growth of the cancer cells. He arranged to obtain some from the company that was working on it, and tried it on his patients. He saw dramatic improvement in some of their symptoms. In the very same week as Canaud’s talk, a group led by an Australian, Ravi Savarirayan, published work showing that a new drug could lead to improved growth and other benefits in children with achondroplasia, the most common type of dwarfism. This kind of conjunction is almost the norm these days: practically every conference we go to includes news of new, targeted treatments for genetic conditions.
[8 This is not normal! Polite applause is usually the best a speaker can hope for. A really good talk might be received with polite applause that goes a bit longer than usual.]
Perhaps most exciting of all, gene therapy is back. In one sense, it never went away. Dedicated researchers around the world have never given up on the idea of an actual cure for many different conditions. For those of us outside the field, gene therapy has had something of the feeling of a perpetually moving goalpost, always ten years away from being reality — until suddenly, in the last couple of years, gene therapies have started to hit prime time. It’s a bit like the musician who is an overnight success — overnight, if you ignore the decades of practice and hard work that preceded their breakthrough album.
The basic principles of gene therapy haven’t changed since the 1990s, when Jesse Gelsinger died. The idea is still to get a working copy of a gene into cells that lack that gene; viruses are still used to transport the new gene to where it needs to go. That means inside the cell nucleus, although not necessarily into the DNA of the cell — in some types of gene therapy, the working copy of the gene sits inside the nucleus and is able to function without having to change the cell’s existing DNA. The decades of work it has taken to make this safe and effective have been about finding the right viruses for the job and modifying them to make them safe but still effective. The modifications stop the virus from reproducing itself, either by removing some important genes or by removing the virus’s own genome altogether, so that it’s only the shell of the virus that is used to deliver the replacement gene to the patient’s cells.
In 2017, the Food and Drug Administration in the United States approved the first ever gene therapy for a genetic condition:9 Luxturna treats a severe eye d
isease, caused by variants in a gene called RPE65. In 2019, the FDA approved a second: Zolgensma is used to treat a progressive neurological condition, spinal muscular atrophy (SMA). There are numerous others on the way — treatments for haemophilia, and for some immune deficiencies. It seems likely that a golden age of gene therapy is just around the corner.
[9 Gene therapy can also be used against cancer — either by directly changing the genes of the cancer cells or by modifying the patient’s immune system so that it can better fight the cancer.]
But … there’s always a but. Luxturna improves vision, but it’s not a cure. Zolgensma has had some dramatic successes, but it can’t reverse damage that has already been done. Michelle Farrar, a paediatric neurologist, and Veronica Wiley, head of the New South Wales newborn screening lab, are leading a study in which newborn babies are screened for SMA. The idea of the study is to try to make the diagnosis before any symptoms develop, and then give gene therapy before damage to the nerve cells has occurred. The hope is that very early treatment may be able to completely cure the condition. We don’t know if this will work, but the idea that it might become possible to take a baby who otherwise would have died in the first year or so of life, give them a single treatment, and cure them, so that they can live a completely normal life, is astonishing; it truly is the stuff of science fiction.
A note of caution is needed. Some of the babies who are identified in the first weeks of life already have symptoms. We don’t know if the effects of the treatment will be permanent, or if treated children might still develop symptoms later on. And even if everything works perfectly, there is bound to be a considerable delay before screening and treatment can become universally available, even in rich countries. We can imagine it might be like the early days of insulin treatment must have been, with a race to get enough of the treatment made and to get it to babies early enough that it will do the most good.
And then there’s the cost.
The first time a patient of mine received enzyme replacement therapy, for a lysosomal storage disorder called Fabry syndrome, I held the bag of fluid containing the drug in my hand while a nurse hooked up the tubing through which we were going to administer it. My patient’s mother pointed out that the contents of that small bag were worth more than her car. This was the first of what will probably be a lifetime of treatments for that boy — now a young man — treatments that are given once a fortnight. The price of a car, every other week. In the case of Zolgensma, you could substitute ‘house’ for ‘car’: the drug costs US$2.1 million for a single dose, the most expensive drug treatment ever made. At least that’s a one-off — over the course of a patient’s lifetime, enzyme replacement therapies work out to be much costlier. There are several of them, including the treatment for Hurler syndrome, that cost hundreds of thousands of dollars per year; over a lifetime, a one-off shot, even at Zolgensma prices, starts to look like a bargain. These high costs are partly because some of these drugs are just very difficult and expensive to make, and partly because the conditions they treat are so rare. If you make a successful asthma drug, it may cost a fortune to develop, but you have good hopes of selling many millions of doses. Treat a condition that affects one person in 100,000 and there’s no way to spread those costs.
All of this means that society may have to face up to some difficult choices. If you have a limited health budget, how best should you spend it? Should you give enzyme replacement therapy to a child with severe Hurler syndrome, knowing that it may improve her quality of life but will not treat her brain disease, and may not greatly lengthen her life? What happens when 20 more such treatments come onto the market?
While some of the new treatments, particularly some types of gene therapy, have the potential to be a cure, it’s likely that most will not. Many of the new treatments may simply turn out to change one problem into another, as with bone marrow transplants for Hurler syndrome. And there are many, many genetic conditions for which there is no realistic prospect of an even partially effective treatment.
It makes you wonder — is there another way?
11
Please, screen me
E pluribus unum (out of many, one)
ORIGINS UNCERTAIN
When Rachael and Jonathan Casella decided it was time to try for a baby, Rachael went to see her doctor, to make sure she was well prepared. The advice her doctor gave her was good, as far as it went. Look after your health; take folic acid, which reduces the baby’s risk of having some serious malformations.1 Once you’re pregnant, you can choose to have a screening test to see if the baby is likely to have Down syndrome — something Rachael went on to do. Unfortunately, however, the advice didn’t go far enough. Not having heard about the option of genetic carrier screening, Rachael’s doctor didn’t tell her about it.
[1 These are called neural tube defects, and they can be very severe. Among others, these conditions include anencephaly, in which the brain, top of the skull, and scalp do not form; and spina bifida, in which the spinal cord is open to the outside, and the amniotic fluid damages the cord, paralysing the baby below the level of the opening. Taking folic acid before pregnancy and in the early weeks of pregnancy greatly reduces the likelihood of having a neural tube defect — it’s one of the great public health wins of the later 20th century.]
Mackenzie Casella was a beautiful baby. Alert and smiley, in photographs her eyes are bright with intelligence. In a better world, she would have grown up into a beautiful young woman, would have gone to school and to university, and would have lived the full life her parents dreamed of for her. In the world as it is, none of those things happened, because Mackenzie had spinal muscular atrophy, and her life was just seven months long.
SMA, as you’ll remember, is a progressive condition that affects the nerves in the spinal cord that control the muscles. In a person affected by SMA, those nerve cells wink out like stars in the dawn sky. Without them, messages from the brain can’t get to the muscles, and the effect is muscle weakness that relentlessly gets worse. When Mackenzie was diagnosed, gene therapy for SMA wasn’t yet an option. Rachael and Jonny were offered the option of taking part in a trial of treatment with another drug, Nusinersen, but they made the difficult decision that this was too uncertain a prospect, and was too likely to leave their daughter — who was already showing signs of weakness that had led to the diagnosis — living with a poor quality of life. So they launched into making their little girl’s short life as full as it could possibly be, giving her all the experiences they could. Snow, sun, sand; every day held something new. Mackenzie’s life was joyful — but from the time of the diagnosis, her parents lived with the knowledge that it would be very short, and so it proved.2
[2 Rachael has written a book about Mackenzie’s life and what happened next, called Mackenzie’s Mission. It’s a moving personal account and well worth a read.]
Mackenzie’s doctor was Michelle Farrar, who has been at the forefront of research into the treatment of SMA. When she first met the Casellas, they asked the questions all parents have when faced with news like this. Why did this happen? Then, when they learned that this was a genetic condition, and that they were almost certainly carriers, they asked — why didn’t we know? Gently, Michelle explained that almost all parents of children with SMA are in the same boat as the Casellas: they have no family history, and only find out they are carriers once the diagnosis is made in their child. There are screening tests available that can identify carriers, and which could have told them that this could happen — but you can only have screening if you know it is an option.
The news shocked and distressed Rachael and Jonny, as it must have shocked and distressed many others in recent years, since screening first became available. But right from the beginning, in the midst of their grief, there was something else: determination. This, they decided, was a situation that could not continue — something needed to be done.
So they set out to do
it.
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Screening for genetic conditions has a longer history than you might imagine, going back more than 60 years. Among the many who have contributed to the story of screening, there are two names of special note — Bob Guthrie and George Stamatoyannopoulos. Of the two, Guthrie is by far the more famous, but perhaps with time the name of Stamatoyannopoulos will become as well known.3
[3 In his later career, Stamatoyannopoulos was a pioneer of gene therapy; his long and illustrious career extended from before the sequence of the first gene was discovered, until a time when gene therapy became a reality.]
I have met perhaps a dozen people with phenylketonuria (PKU). Of those, only one has had the classical features of this rare condition. Frank was a man born in the 1930s, before newborn screening for PKU began. At the time I knew him, he was in his 60s and had never learned to speak. His head was very small, he had a history of seizures, and the staff at the institution where he lived reported that he was often aggressive.
By contrast, all of the other people with PKU that I have met have been well, healthy children or adults, with normal intelligence and no neurological problems. The contrast between them and Frank could not have been more stark, and the reason for it was that they had all been screened for PKU in the first week of their lives. The early diagnosis had made it possible to start treatment immediately, and completely prevent the damage to their brains that otherwise would have been inevitable.
PKU is another metabolic condition, a disorder of the body’s chemistry, and it has to do with how the body deals with an amino acid called phenylalanine. Our bodies use amino acids to build proteins, and, in turn, when we eat foods that contain protein, we are consuming amino acids. In most of us, an enzyme converts the phenylalanine we eat into another amino acid, tyrosine. In people with PKU, that enzyme doesn’t function properly and levels of phenylalanine soar.