We spoke to Dr. Thomas Wishart of the Roslin Institute about the team’s latest findings.
What is Batten disease?
Batten disease is a term for a group of diseases also known as neuronal ceroid lipofuscinoses or lysosomal storage disorders. These are conditions where patients carry mutations or defects in genes that end up affecting the function of the lysosome, which is the cells’ waste disposal and recycling system. Lysosomal storage disorders are generally considered the most common form of dementia in children.
There are 14 different forms of the disease that we know of. These are what we call neurodegenerative diseases and affect the form and function of the nervous system. This is called a rare disease. In the UK there are maybe 100, 150 patients at the moment. But of course, that doesn’t make it any less impactful for people who have it and their caregivers.
Does the disease affect children from birth?
Not necessarily. As I said, there are 14 different forms and they all affect the function of lysosomes, this waste disposal and recycling system in the cell. Thus, the majority of presentations are similar, the main difference being the time of onset – the age at which they begin to get sick and how long it lasts before they unfortunately die prematurely.
The form of the disease we were talking about, which is called the CLN1 form of the disease, is quite early onset. Generally, the first presentation of the disease is that the children, unfortunately, become blind. Then they will have more basic cognitive deficits – changes in their thought processes or their ability to retain information or develop new memories, then also their ability to interact with family members. They develop motor changes, that is, their ability to move and coordinate their abilities. And normally they will end up in a wheelchair pretty quickly and then lose their mobility. Ultimately, most of these children will die before the age of 10.
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So your work is centered on the disease caused by a faulty CLN1 gene?
Yes. Each of the different forms of Batten disease affects a different gene that impacts lysosome function. For this form of the disease, the gene is called CLN1. It is believed to produce an enzyme called PPT1, which plays a role in the function of lysosomes.
You then genetically engineered sheep to carry this defective gene and treated them with the missing enzyme?
Our collaborators in the United States already have a mouse model for this particular disease. Mice are useful tools for doing some basic biology work, but they don’t look much like humans and that’s a big deal right now. In broad terms, we call this translation – moving something from a rodent-derived therapeutic to something that will actually be clinically effective. We need an intermediate model system, if you will, to be able to show that we can actually scale.
In the nervous system of a mouse, if you place the enzyme in the fluid-filled spaces of the brain, the ventricles, the maximum distance it has to travel to get full coverage of the brain is only two or three millimeters in any direction. If you want to do it in a child’s brain, then it has to be two centimeters in every direction.
So just because we can do it on a mouse doesn’t necessarily mean it’s going to be effective on a human.
To be clear, and I think when we try to stress this point, no one wants to do big animal therapeutic research. But there’s no alternative to showing that you can actually transition from small-scale therapy to something that will actually be effective in the clinic.
Where is the research?
Our collaborators in the United States had shown this to be a viable route to essentially rescue the disease in a mouse model.
We were able to basically show that if we increase the delivery of this therapy into the brains of the sheep, again into the fluid-filled spaces of the brain, and we give this month, we can change the progression of the disease .
What are the next steps?
It’s very, very early. It’s proof of principle that it’s worth pursuing and is probably a viable avenue for developing a therapy. The next steps are to try to secure funding to do this on a larger scale and to essentially refine the protocol for administering the therapy. How much enzyme should you give? How often should you give it? And where exactly should you place it in the first place?
It should be remembered that this is far from therapy now. It’s an effective proof-of-principle and it’s promising, but it’s going to be a while before anything goes to patients.
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