Two teams of researchers have independently converged on a new drug target for Parkinson’s disease. Two studies published last week, one from the biotech start-up Yumanity Therapeutics and another led by the lab of Dennis J. Selkoe at Brigham and Women’s Hospital and Harvard Medical School, both discovered that small-molecule inhibitors of a fatty acid–metabolizing enzyme could alleviate the toxic effects of a protein implicated in the neurodegenerative disease.
Despite decades of research, scientists still don’t fully understand what causes Parkinson’s disease. One culprit is a protein called α-synuclein. The protein hangs around the lipid membranes of cells, but it’s not entirely clear what its normal function is. In Parkinson’s, misfolded forms of α-synuclein form toxic clumps inside brain cells, and rare genetic mutations that increase α-synuclein levels are linked to inherited forms of the disease. This has made reducing α-synuclein a popular strategy for drug developers.
α-Synuclein’s floppy, unstructured form has made it difficult to target with standard small molecule drugs, so most ongoing drug programs target the protein with antibodies. But these experimental antibody therapies face two big hurdles: Antibodies struggle to enter the brain and to slip into cells, where α-synuclein clusters. “There’s been virtually no handle on how you would treat the disease with a small-molecule therapy,” Selkoe says.
The studies from Yumanity and Selkoe present a new, unexpected way to reduce toxic α-synuclein levels with a small molecule. The two teams concluded that increased levels of a monounsaturated fatty acid called oleic acid, found in cell membranes, aggravates α-synuclein’s toxicity. Using small molecule compounds to inhibit the activity of an enzyme called stearoyl-CoA desaturase (SCD), which makes oleic acid, eliminates α-synuclein’s toxic effects in cells. The strategy is totally different from any other intervention ever attempted for Parkinson’s disease, and Yumanity plans to test the idea in humans by the end of next year.
“This is an exciting development in the field of α-synuclein therapeutics and Parkinson’s disease,” says Subhojit Roy, a neuroscientist at the University of Wisconsin who was not involved in the study. He is also encouraged that two papers, with different approaches, arrived at the same target. “While the effect of α-synuclein on lipids has been known for some time, therapeutic strategies exploiting this property have been few and far in between,” he adds.
Both groups started by using yeast to uncover the link between SCD and α-synuclein. Yumanity, a biotech startup that raised $45 million in 2016, was founded on the idea that yeast could provide a quick way to find new targets and therapies for neurodegenerative diseases. Their program targeting SCD “is the first publicly disclosed output of that discovery engine,” says Chief Scientific Officer Kenneth Rhodes.
Yeast don’t normally make α-synuclein, so scientists at Yumanity introduced the human gene for the protein into yeast cells. As the cells produce the protein, it impedes their growth. This fact allowed the team to set up an easy-to-follow screen in which the researchers exposed the yeast to a library of small molecules to find a compound that allowed the cells to grow in the presence of the toxic α-synuclein. A collection of compounds containing a core 1,2,4-oxadiazole structure rescued the yeast from the α-synuclein toxicity and reduced the protein’s aggregation in the cells (Cell Rep. 2018, DOI: 10.1016/j.celrep.2018.11.028).
Next, the team had the more arduous task of figuring out what their best-performing oxadiazole compound was doing inside the cells. Yumanity looked for yeast that weren’t rescued by the compound, indicating that the cells carried a mutation that prevented the compound from working. The team found several such mutant yeast, all of which had mutations in a gene called OLE1. The human equivalent of OLE1 is SCD1, which encodes a variant of the SCD enzyme.
The second study, led by Selkoe, reached similar conclusions about SCD. Parts of the study were also completed in the lab of Susan Lindquist, former director of the Whitehead Institute for Biomedical Research, who died in 2016. Lindquist developed yeast-screening methods that were exclusively licensed to Yumanity.
The Selkoe and Lindquist team started by expressing human α-synuclein in yeast to see how its expression altered the cells’ lipid profile. They observed increases in unsaturated fatty acids, particularly oleic acid. Directly adding oleic acid to cells intensified α-synuclein toxicity, and lowering levels of the oleic acid–making enzyme Ole1 relieved α-synuclein toxicity.
Next the group tested the effects of reducing oleic acid in rat and human neurons grown in a lab, a Parkinson’s worm model, and a Parkinson’s mouse model. In all cases, the enzyme that makes oleic acid—SCD in humans—emerged as a promising drug target for reducing α-synuclein toxicity (Mol. Cell 2018, DOI: 10.1016/j.molcel.2018.11.028).
“The results are pretty dramatic,” but not a complete surprise, says Robert Edwards, a neuroscientist whose lab is studying α-synuclein at University of California, San Francisco. Lindquist showed that α-synuclein interacts with cell membranes 15 years ago, he says. “That interaction becomes even more clear and prominent as time goes by.”
The papers, although promising, raise several questions, Edwards says, such as why α-synuclein expression would raise oleic acid levels. “Synuclein by itself seems to do something to membranes, but it’s not clear why it does that or what it means,” Edwards says. Selkoe says his lab is investigating these questions.
Edwards adds that blocking SCD could alter the lipid composition of cells throughout the body. The consequences of that are not known, but Yumanity thinks the strategy should be safe because drug companies have already studied SCD inhibitors as antiobesity drugs. Those drugs never made it to market because they were not effective for weight loss, but Yumanity’s Rhodes notes that there were no safety concerns in clinical trials of the drug.
Yumanity plans to test a drug candidate called YTX-7739 in a Phase I clinical trial next year. The startup isn’t disclosing the structure of this compound, but Rhodes says it is chemically distinct from the oxadiazole compounds presented in their paper. The compound was also designed to target a variant of SCD called SCD5, expressed primarily in the brain and more strongly than SCD1, which is found throughout the body.
Time will tell if this approach will have more success than programs targeting α-synuclein directly, which are in early-to-mid-stage clinical trials. The new strategy has “a rationale, and a lot of things tried in Parkinson’s disease have a pretty weak rationale,” Edwards says. “It has to do with synuclein, so it’s getting close to the heart of the matter.”