by Jo Kaur
These days, my thoughts are filled with mice. It all comes down to the mice. Here’s why.
Mice, as it turns out, are critical in the development of a treatment. In order for us to convince the FDA to administer a treatment to children, we must first test it on diseased mice to ensure that it helps them. Mice are not people, but they provide a lot of insight as to whether a treatment is effective or safe. The treatment in this case is gene replacement therapy, specifically using a viral vector to deliver a copy of the healthy gene into children’s bodies. I will refer to the treatment as a “vector” from here on out.
In this case, we want to test the vector on mice who have Cockayne Syndrome, specifically mutations in CSA (the same gene that is mutated in Riaan and other children with his diagnosis). CSA is a gene that is involved in the process of DNA repair and transcription.
What is interesting about Cockayne Syndrome mice is that they have milder neurological symptoms than humans. They don’t experience the same “tragedy in the Central Nervous System” that babies do. This is a remarkable feature of nature. So what do we do? How can we test the vector on animals with milder features?
It turns out there is a work-around. Mice who lack two DNA repair genes, CSA and another gene called XPA, do exhibit many of the severe symptoms, including neurological abnormalities, found in humans. These mice are very sick. They live for only 28 days, which can be extended to 16 weeks with a soft chow diet. No model will be 100% perfect but it gives us some idea of what we may expect to see from the treatment in children.
There is another mice model too that shows severe symptoms of Cockayne Syndrome. These mice are missing another DNA repair gene called XPG, and are more documented in the literature so they can provide a useful analysis for comparison. The XPG mice are born “normal” but then their growth quickly slows down, similar to human babies. They begin to waste away, with severe motor deficiency and muscle weakness, their Purkinje cells (a form of neurons) degenerate and die, there is cell death in their retinas leading to vision degeneration, their organs are smaller in size, and their liver shows symptoms of accelerated aging.
The XPA mice with severe symptoms of Cockayne Syndrome, the disease Riaan has, die between 15-18 weeks (3-4 months). By way of reference, typical, healthy mice without any disease live between 12-18 months.
This pattern we see in mice is similar to what we see in humans. They live short lives, waste away, and experience multi-system degeneration and failures.
Cockayne Syndrome is an alarming disease to be taken very seriously. It is hard to believe something so vicious can attack our babies.
Our hope is that when we test the vector (gene replacement therapy) on the diseased mice, they will live longer, they will be healthier and active, their organs will weigh more, the degeneration will be halted or even reversed (we certainly hope to see this in humans), and we’ll see a reduction in symptoms. There is good reason to believe we’ll see this result, and other promising (unpublished) studies that indicate we are on the right path. We also want to ensure that there are no unusual or toxic reactions in the mice from the vector.
But as with all scientific experiments if you remember from high school, we can hypothesize as much as we want. We won’t know for sure until we actually run the experiments. And experiments are expensive.
Donate today at riaanresearch.org/donate, and help us fund this critical research. Let’s save some lives.
Thank you also to everyone who has supported this work so far. We are grateful!