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the amount of GCase in a Parkinson patient’s peripheral blood cells makes a good biomarker—that is, a stand-in for the disease to help LTI choose people for their trials who are more likely to respond to a GCase-boosting drug.
Been told Xconomy last year that the second main goal in LTI’s early days was better understanding the biology driving the GCase-synuclein seesaw effect.
LTI’s chief scientific officer Peter Lansbury explained some of the biology that is slowly revealing itself, and how LTI wants to treat it. The two proteins exist in a network that also contains several other enzymes involved in lysosomal storage disorders. (There are roughly 50 such ailments in all, including Gaucher, Fabry, and Pompe disease.)
The network seems to compensate for a certain amount of disturbance to one of its members, but the push-and-pull of GCase and synuclein seems to have a threshold. “You can have lower and lower levels of GCase without having disease,” said Been. “But only until you hit a particular level does the level of synuclein come up. It’s an interesting phenomenon.”
Lansbury used the analogy of a river system in which the flow of water can compensate for some blockages, until a certain dam causes flooding elsewhere. “I think of that as the toxic part of the cascade,” said Lansbury. “Most drug targeting is done in a narrow way, where you target a specific step. Our point of attack is GCase, but we want to understand what happens to the whole system. People who usually do this design traffic patterns or worry about river flows. We’ve got some applied math guys we want to start working with on this.”
(For the record, the network in question is called the glycosphingolipid degradation pathway.)
It’s always exciting to delve into molecular mysteries, and LTI is certainly doing that. But Been has been around the block a few times. He’s a veteran of Biogen Idec who then ran EnVivo Pharmaceuticals for eight years until he stepped down in 2013. (Forum is now known as Forum Pharmaceuticals and run by Deborah Dunsire.)
Been keeps the conversation grounded when asked if new biological insights could help LTI test its drug in people before they even show symptoms, Been said, “The FDA will need to see a clinical effect, either a symptomatic or disease-modifying improvement. Ultimately we have to run the $150 million experiment in Phase 3.”
And that price tag can only be covered by a much bigger company, which is why LTI will need to find a development partner, said Been. “There’s no escape.”