Life-saving gene therapy for UK baby

This week scientists announced that a toddler with a rare, fatal genetic condition has been treated successfully with a new gene therapy approach. 19-month old Teddi has MLD - metachromatic leucodystrophy. This is an inherited disease linked to a defective gene that normally codes for an essential enzyme called arylsulfatase A. Without this working, material builds up inside certain cell types and causes them to die. The developing brain is particularly vulnerable and affected individuals become progressively more disabled and usually don't make it past the age of 5. In Teddi's case, the Royal Manchester Children's Hospital's Rob Wynn and his colleagues have - they think - hopefully effected a cure. They've taken stem cells from her bone marrow and altered them in the lab to add back in a healthy copy of the gene, as well as some control information to supercharge its activity, leading to high level production of the missing enzyme. Those modified stem cells were returned to Teddi where they migrate to the bone marrow and produce blood and immune cells. Some of these then migrate into the nervous system where they pump out the enyzme for other cells to use…

Rob - In illnesses like MLD, where there is a deficient enzyme, we can use bone marrow transplantation to help the condition. And what happens there is the normal healthy bone marrow makes normal healthy blood, makes the enzyme and delivers that enzyme around all tissues of the body, including in the brain. We know when we do a bone marrow transplant in MLD, actually it doesn't correct the condition, and we've understood in recent years that's because normal healthy blood does not give enough enzyme in this condition. So we take blood stem cells from the patient and in the laboratory we insert the missing copy of the gene. Now we do that using a virus, but we have modified that virus. So when it infects their blood stem cell, instead of delivering virus DNA, they deliver the enzyme gene. But we've also made one other key difference. Genes in our cells are controlled in a very tight way. And actually the MLD gene is controlled in a very tight way in blood stem cells. And this is a why a normal bone marrow transplant does not give enough enzyme because the gene is turned off, the blood doesn't need to make a lot of enzyme. So when we use gene modified cells, not only have we put in a healthy copy of the gene, but we have changed the promoter next to that gene that tells the gene to be turned on. And so the gene modified stem cells make vastly more enzyme and because more enzyme is good for the disease then we actually see that this makes the illness better. Whereas a normal bone marrow transplant doesn't.

Chris  - These are bone marrow stem cells, so they're going to be making elements of the blood and they're going to be outside the brain. There's a barrier in place that keeps the brain tissue and the blood tissue compartments separate, it's called the blood-brain barrier. So how does making the bloodstream awash with this missing enzyme get the brain treated?

Rob - This is an excellent question. It actually goes to the heart of why bone marrow transplant in cell therapy corrects neurologic enzyme deficiencies in a way that drug therapy does not. Cells can cross the blood-brain barrier and engraft, and wide cells becoming engrafted in the brain where they're known as microglia. So if we do a gene modified blood stem cell transplant, then we will get gene modified wide cells, they will cross the blood-brain barrier and then become engrafted in the brain. And so gene modified brain engrafted microglia make the enzyme that the patient needs and forever.

Chris - And when they're sitting in the brain, they're presumably secreting the missing enzyme into the milieu there and what the dependent cells that would normally be missing, it can pick it up and use it.

Rob - This is exactly the principle of transplantation in this type of disease and it's known as cross correction. The engrafted donor cells make and secrete enzyme. That enzyme is taken up by neighbouring cells that remain genetically enzyme deficient, but they're able to take up this secreted enzyme and metabolise within their cytoplasm accumulated substrate.

Chris - Is the prognosis then, for this young lady, a very good one in the sense that as long as she stably continues to have these cells making this stuff in her brain, then she should remain well?

Rob - We think that this girl can look forward to a normal life expectancy in a normal quality. So clearly using gene modified stem cells in MLD is new. However, we have a wealth of experience of using transplants from donors in similar diseases. And what we see in those illnesses is that the effect on the condition is lifelong. So we have every reason to be optimistic that the gene modified stem cells will also similarly dramatically change this young girl's life.

Chris - Are there any risks here? In the past, when people have used viruses to change stem cells in this way, they've been concerned that when you are adding bits of DNA to a cell's own DNA you can make cancers, and also if they are churning out huge amounts of this material that they wouldn't normally churn out into the bloodstream, are there any health risks from that?

Rob - Certainly all of our medical decisions are based on balance of risk. This is a disease associated with premature death and children are dying in early life and before dying they lose their skills that they had acquired. So risk balance is very much in favour of this treatment. Viruses insert their DNA into our DNA and this is why there is some cancer risk. If they insert their DNA next to what we call an oncogene that's associated with controlling cell proliferation, they can cause cancer. But the virus vector, as we call it here, is so modified that it inserts randomly into the genome, and if it inserts randomly then it's much less likely to cause cancer. In terms of the enzyme overexpression, that's a very important point. The very basis of this treatment is that the gene modified cells make much more enzyme in the blood. So in our preclinical work, we have been able to show that that enzyme expression, that enzyme overexpression as we call it, does not affect blood stem cell function. And so the cells are able to engraft and the cells are able to make blood that is otherwise normal.