150 times more effective medicine for critically ill children
Every year, one in about 5 000 children is born with a rare gene mutation that affects the function of the cell's lysosome. This can lead to disability or premature death. Researchers at KTH have developed a way to produce 150 times more effective versions of the drugs these children so desperately need.
Lysomal storage diseases is the collective name for the diagnoses that several children worldwide are born with each year. They are caused by a rare mutation in one of several vital genes. These encoding enzymes help our cells break down cellular waste products in the lysosome. The cells swell and lose their function, which can lead to severe chronic disability or, in the worst case, premature death.
Very small amounts naturally
For the children to live as normal a life as possible, they need a replacement supply of the missing enzyme. Enzyme production is done by growing living cells in bioreactors, known as cell factories, where the enzyme is purified.
One problem is that the natural synthesis of the enzyme in each cell is very small, and the cell's "machinery" is not designed to produce the enzyme at scale very efficiently.
"In previous attempts to increase cell production, only a small proportion, perhaps only a few percent of the enzyme produced has been of the right quality and in the so-called active form. This low activity presents several challenges. Patients need to take a higher dose of medicine more often, and production costs are high. In addition, the risk of side effects increases with a high dose of a drug that is not fully active," says Johan Rockberg, professor at the Division of Protein Technology at KTH and one of the researchers behind the work.
Two different cell factories
In order to find a solution to the problem, he and the other researchers used the transcriptomics method to study two different cell factories. The first with a high enzyme production but low quality and activity of the enzyme, the second with lower productivity but higher enzyme activity. Under carefully controlled culture conditions, the researchers have managed to find cellular processes and groups of genes linked to the increased production quality.
"Our analysis has led us to focus on the so-called secretory signaling pathways where enzymes are modified by helper proteins before being sent out of the cell," says Rockberg.
By using synthetic biology to increase the expression of one of these helper proteins in the cell factory, the researchers were able to improve the activity of the produced drug enzyme 150 times.
"We hope this will lead to more cost-effective medicine production so that more people can benefit from these drugs, but also with potentially reduced side effects and possibility to lower injection volumes or make use of other routes of administration," says Rockberg.
The project was financed by funds from Vinnova, Knut and Alice Wallenberg's foundation and SSF.
Text: Peter Asplund
For more information, get in touch with Johan Rockberg at 08 - 790 99 88 or johanr@biotech.kth.se.