“Krabbe disease is rare,” says Farah, “affecting one in 100,000 births, although in some closed populations, such as the Druze and Arab communities in Israel, it may be as common as one in 150 births.”
Affected babies initially seem healthy, then develop symptoms such as seizures between one and three months after birth.
Krabbe disease belongs to a family of diseases caused by a particular defective or deficient enzyme, which is usually responsible for breaking down accumulating lipids in the brain. Without this enzyme, the lipids build up to a level that is toxic for brain cells.
“There have been great breakthroughs in treating other diseases caused by defective enzymes, by using enzyme-replacement therapy, but this doesn’t work for Krabbe disease because the replacement enzymes are too big to cross the blood–brain barrier,” says Farah.
“Our aim is to develop a general approach for their design that will lead to a treatment for Krabbe disease and may also be applied to other neurodegenerative diseases caused by defective enzymes.”
While working on her PhD in France, she came across the work of the Ferrier Research Institute’s Professor Peter Tyler and wondered if the techniques he was developing would work with diseases such as Krabbe disease.
“Chaperone-mediated therapy works by restoring the activity of partially defective enzymes, using a small molecule called a pharmacological chaperone,” she says. “The damaged or deficient enzyme is folded into the right shape and a ‘chaperone’ helps transport this mutated enzyme to where it needs to be so it can do what it needs to do. The chaperone is then displaced.”
The challenge is to get a chaperone that is strong enough to do the job, but not so strong that it can’t be displaced at the right time. To achieve this, Farah and colleagues Dr Scott Cameron and Dr Wanting Jiao will use a technique that has been used to design powerful enzyme inhibitors, but never previously used to design pharmacological chaperones.
"Our aim is to develop a general approach for their design that will lead to a treatment for Krabbe disease and may also be applied to other neurodegenerative diseases caused by defective enzymes," says Farah.
She says there is still a long way to go. “We got funding from the Ministry of Business, Innovation and Employment’s Smart Ideas fund in 2019 and last year received more support from Cure Kids to help with the computational work, which should allow us to shorten the time between design and synthesis of the molecule.
“We hope to have something good to show within the next few years.”
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