[Updated 5/12/14 10:30 pm. See below.] It’s been known for a while: Patients with the rare Gaucher disease are at much higher risk for Parkinson’s disease, as well.
But only recently have drug makers, like Lysosomal Therapeutics (LTI), set out to turn that knowledge into a Parkinson’s treatment. LTI said Monday it has secured a $4.8 million seed commitment from a syndicate led by Atlas Venture. Though it called the news its debut, the startup hasn’t exactly been stealthy, what with biotech heavyweight Henri Termeer acting as co-founder, mentor, and early spokesman.
The link between Gaucher and Parkinson’s has come to light because of Termeer’s past. At the helm of Genzyme, he helped turn the Gaucher treatment imiglucerase (Cerezyme) into a huge business the past two decades and built the foundation for today’s rush to find drugs for rare diseases.
As Gaucher patients began living longer, their doctors noted a great incidence of Parkinson’s. That connection has been borne out by genetic studies at the National Institutes of Health and elsewhere.
In 2011 while at Harvard University, LTI scientific cofounders Dimitri Krainc and Joseph Mazzulli, now both at Northwestern University’s Feinberg School of Medicine in Chicago, IL, published work that showed a “bidirectional pathogenic loop” between glucocerobrosidase, or GCase, the enzyme linked to Gaucher, and the protein α-synuclein that clumps up in the brain cells of Parkinson’s patients. The less active GCase is, the more α-synuclein builds up: Break that loop, the thinking goes, and perhaps a Parkinson’s treatment will emerge.
LTI isn’t the only entity to pursue Parkinson’s along these relatively new lines. Cranbury, NJ-based rare-disease drug developer Amicus Therapeutics (NASDAQ: FOLD) inked a deal with Biogen Idec (NASDAQ: BIIB) last September to develop small molecules that target GCase. Amicus has previously tried to treat Gaucher by targeting GCase with small molecules—fixing the faulty enzyme instead of infusing patients with replacement enzymes—but that program failed in 2009.
Gaucher disease is caused by a genetic mutation that makes GCase misfold and no longer able to do its job: clearing the fatty substance glucosylceramide from cells. The resulting buildup can result in early childhood death or a slower disease progression, depending on the type.
While Amicus managed to get GCase into the lysosome, the part of the cell where it’s needed to break up the fatty glucosylceramide, its drug inhibited GCase and kept it from doing its job. Krainc says LTI aims to develop oral drugs that get GCase into the lysosome and keep it active to break that feedback loop with α-synuclein. [A previous version of this story said LTI scientists designed their program to learn from Amicus’s example, but Krainc says he had a program in development before he had heard of Amicus.]
LTI doesn’t have a huge cash commitment, but right now it’s only working toward two goals, says CEO Kees Been. First, it wants to better understand the biology of the feedback loop, and specifically what happens when GCase is activated. Second, it wants to refine the compounds it licensed from the NIH that have shown they can activate GCase, but don’t yet have “drug-like” properties.
At least some of that work will take place in human neurons that were derived from Parkinson’s patients via induced pluripotency (the process that “rewinds” specialized cells — such as ordinary skin cells — back into undifferentiated stem cells, which in turn can be directed into a new, specific cell type). It’s relatively new, and one of the ways the stem cell revolution in biology has begun to affect the biomedical landscape.
LTI’s Been, previously CEO of Watertown, MA-based EnVivo Therapeutics (now known as Forum Pharmaceuticals), points out that the traditional use of mouse models for neurodegenerative disease R&D hasn’t produced many breakthroughs. There’s hope that real human cells that have the disease’s characteristics will be more accurate test-beds. “[Induced] neurons from a patient might be more predictive,” says Been.
Joining Atlas Venture in the round are Hatteras Venture Partners, Lilly Ventures, Sanofi-Genzyme BioVentures, Roche Venture Fund, Partners Innovation Fund, and angel investors.
Henri Termeer photo courtesy Robert Scoble via a Creative Commons license.