HORIZONS
GENE-EDITED SHEEP OFFER A GLIMMER OF HOPE IN DEVELOPING A TREATMENT FOR A FORM OF CHILDHOOD DEMENTIA
Scientists at Edinburgh’s Roslin Institute have created sheep that carry the gene for Batten disease, a rare and fatal childhood illness for which there is currently no cure. Dr Thomas Wishart tells us more
WHAT IS BATTEN DISEASE?
Batten disease is a term for a group of diseases which are also known as neuronal ceroid lipofuscinoses, or lysosomal storage disorders. These are conditions where patients carry mutations or faults in genes that ultimately end up affecting the function of the lysosomes, which are the cells’ waste disposal and recycling system. Lysosomal storage disorders are generally referred to as the most common form of dementia in childhood.
There are 14 different forms of the disease that we’re aware of. They are what we call neurodegenerative diseases and affect the function of the nervous system. It’s a rare disease. In the UK, there are maybe 100 or 150 patients at the moment. But obviously that doesn’t make it any less impactful for those people who have it and their carers.
DOES THE DISEASE AFFECT CHILDREN FROM BIRTH?
Not necessarily. As I said, there are 14 different forms and they all affect the function of the lysosomes, this waste disposal and recycling system in the cell.
The majority of the presentations are similar, with the main difference being the time of onset – the age at which they start to get sick – and how long that goes on for before they die prematurely.
“This is a proof of principle that is worth following up and is likely to be a viable route to developing a therapy”
The form of the disease that we are talking about, which is called the CLN1 form of the disease, is quite early onset. Typically, the first presentation of disease is that the kids, unfortunately, go blind. Then they’ll have more core cognitive deficits, such as changes in their thought processes, or their ability to retain information or develop new memories, and their ability to interact with family members.
They develop motor changes, which means that their ability to move around and coordinate their abilities is affected. And normally they’ll end up in a wheelchair quite rapidly and then lose mobility. Ultimately, most of these children will have passed away by the time they’re 10 years old.
SO YOUR WORK IS CENTRED ON THE DISEASE THAT IS CAUSED BY A FAULTY CLN1 GENE?
Yes. Each of the different forms of Batten disease affects a different gene that impacts on lysosome function. For this form of the disease, the gene is called CLN1. It is supposed to produce an enzyme called PPT1, and that plays a role in lysosome function.
YOU THEN GENETICALLY ENGINEERED SHEEP TO CARRY THIS FAULTY 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 for carrying out some basic biology work, but they are not much like people and that’s a big problem at the moment. In general terms, we call it translation – moving something from rodent-derived therapeutics into something which is actually going to be effective in the clinic. We need an intermediate model system, if you like, to be able to show that we can effectively scale up [from small to large].
In the nervous system of a mouse, if you put the enzyme into the fluid-filled spaces in the brain, the ventricles, the maximum distance it has to travel to get complete coverage of the brain is only two or three millimetres in any direction. If you want to do it into the brain of a child, it then has to go two centimetres in every direction. So, just because we can do it in a mouse, it doesn’t necessarily mean that it’s going to be effective in a human as well.
To be clear – and I think we try and stress this point – nobody wants to do large animal therapeutic research. But there’s no alternative for showing that you can effectively make that transition from small-scale therapy to something that is actually going to be effective in the clinic.
HOW FAR ALONG IS THE RESEARCH?
Our collaborators in the States have shown that this is a viable route for essentially rescuing the disease in a mouse model. We’ve managed to show that if we scale up the administration of this therapy into sheep, again into the fluid-filled spaces of the brain, and we give this therapy monthly, then we can change the progression of the disease.
WHAT ARE THE NEXT STEPS?
It’s very, very early stages. This is a proof of principle that is worth following up and is likely to be a viable route to developing a therapy. The next steps are to try to get funding to do this on a larger scale and essentially refine the therapy administration protocol, to try to answer questions like, how much enzyme do you need to give? How often do you need to give it? And where exactly should you be putting it in the first instance?
It is worth reiterating that this is far from being a therapy now. This is an effective proof of principle and it’s promising, but it will be a while before anything is going to go into patients.
DR THOMAS WISHART
Thomas is a reader in molecular anatomy at the University of Edinburgh’s Roslin Institute. He studies the mechanisms underpinning neuronal development and degeneration.