When his company raised nearly $5 million in seed funding last year, Lysosomal Therapeutics founder, president, and CEO Kees Been said he had two goals: learn more about the underlying connection between the rare Gaucher disease and Parkinson’s disease, and sort through compounds licensed from the National Institutes of Health to find the best one to turn into a Parkinson’s drug.
The Cambridge, MA-based startup has reached the second goal. It has found its compound and is ready to move it ahead in preclinical studies. The work will be fueled by a Series A round that could close by the end of the month, Been (pictured) said during an interview at the J.P. Morgan conference in San Francisco.
Atlas Venture led LTI’s seed round last year, and former Genzyme CEO Henri Termeer with three other Genzyme alumni were cofounders. Genzyme pioneered enzyme replacement therapy that has extended the lives of patients with Gaucher, a hereditary disease caused by a deficiency in the enzyme glucocerebrosidase (GCase). As Gaucher patients began to live longer, their doctors started noticing that they had a greater than normal incidence of Parkinson’s.
That connection has been borne out by genetic studies at the National Institutes of Health and elsewhere. LTI was founded to exploit the link between levels of GCase and α-synuclein, the protein that clumps up in the brains of Parkinson’s patients.
The link is more like a playground seesaw. When one goes up, the other goes down. In Gaucher patients, a mutation in the gene for GCase prevents it from clearing a fatty substance from cells, which eventually die. Low levels of active GCase also correlate to high levels of damaging synuclein.
LTI is betting the reverse will be true: Boost healthy GCase with a drug, and Parkinson’s patients will benefit as synuclein clears out. LTI has competition. Amicus Therapeutics (NASDAQ: FOLD) of Cranbury, NJ, is working on the problem, and its research in the area is under license to Cambridge, MA-based Biogen Idec (NASDAQ: BIIB).
Researchers at the University of California, Los Angeles, recently found that an Amicus drug being tested against Gaucher has shown promise for Parkinson’s—albeit only in mice so far.
Part of LTI’s confidence in its own approach comes from work by its scientific founder Dmitri Krainc of the Feinberg School of Medicine at Northwestern University, who has studied its compounds in neurons derived from an extremely rare group of Parkinson’s patients. Those neurons had three copies of the synuclein gene, which meant they produced an overabundance of the damaging protein. But when treated with one of the test compounds, the cells’ synuclein production dropped.
There’s still a ways to go before human testing, however. First, chemical modifications are required to “optimize” the lead compound—make it behave more like a drug. While LTI is doing that, it will also run experiments to see if 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.”