Using yeast to help uncover new disease targets and some new developments in prion disease. Our live coverage of the 2nd World Congress  

Saccharomyces cerevisiae, a species of yeast instrumental in winemaking, is one of the most extensively studied eukaryotic model organisms in molecular and cell biology. It turns out that yeast is also a reliable system for identifying novel compounds that could potentially fix the protein misfolding pathologies that trigger Alzheimer’s, Parkinson’s and other neurodegenerative disorders.

Just ask Ken Rhodes PhD, Chief Scientific Officer at Yumanity Therapeutics, one of a dozen presenters at Charles River’s 2nd World Congress, a two-day meeting focused on rare disease research.

Yumanity, whose name derives from a coupling of Yeast and Humanity—is a young Cambridge-based biotech employing about 40 individuals. The company takes advantage of the relative simplicity of the yeast genome and the high conservation of molecular pathways between yeast and mammals to screen for compounds that can keep cells alive in the presence of toxic aggregates, such as the toxic amyloid beta and tau associated with Alzheimer’s disease or alpha- synuclein associated with Parkinson’s. Their work has led to about a dozen new targets that can be modulated and a lead program that is on track to enter clinical testing in 2019.

“Yumanity was formed to tackle some of the greatest therapeutic challenges of our age,” said Rhodes. “Alzheimer’s and Parkinson’s aren’t rare, unfortunately, but the pathophysiology particularly in Parkinson’s, can give us deep insights into other rare forms of disease, such as Lewy body dementia.”

Yumenity is building on the research started by visionary biologist Susan Lindquist, Director of the Whitehead Institute for Biomedical Research from 2001-2004 and co-founder of Yumanity in 2015. Lindquist passed away last year at the age of 67.  In 2003, Lindquist’s laboratory published a paper that modeled a key pathology of Parkinson’s disease in yeast by over-expressing alpha-synuclein. She followed up 10 years later with two papers that described a platform using yeast cells, high-throughput screens and induced pluripotent stem cells that paved the way for Yumanity two years later.

To find targets, researchers at Yumanity take pooled collection of DNA bar-coded mutants—where an individual gene in yeast is replaced with a unique DNA molecular DNA barcode—and expose the pooled barcodes to a compound.  The yeast is then grown for 24-48 hours, and the barcodes sequenced to help identify which gene mutation offers either a growth advantage or a growth defect. “We take all that information to get from a screening hit to either a specific molecular target or a small collection of targets within a pathway,” says Rhodes.

They have already encountered some success with the alpha synuclein platform. Using high-toxicity alpha synuclein screens, researchers at Yumanity got some early hits and identified a potential target, a previously identified enzyme that had never before been associated with Parkinson’s. Using these platforms they are making strides headway with ALS and Alzheimer’s.

“We have had a very interesting journey,” concluded Rhodes. “We brought a compelling set of biological tools and technology platforms into the company from Sue’s lab at the Whitehead. The real question was could we industrialize it to meet a robust drug discovery effort I think we’ve demonstrated that.”

Two Steps Forward

Last year, the inaugural World Congress honored a young research couple racing to find a cure for a rare disease that has tremendous implications for both of them. Sonia Vallabh and Eric Minikel of the Broad Institute of MIT and Harvard, the first recipients of the Charles River Research Models in Drug Discovery Award, are studying the rare prion disease, fatal familial insomnia, that killed Vallabh’s mother and which now poses a risk to Vallabh.

Since last fall, they have partnered with Ionis Pharmaceuticals in Carlsbad, California to develop an antisense oligonucleotide (ASO) therapy, which work by targeting complementary RNA sequences for destruction. Ionis, which has been developing ASOs for other rare disorders—it recently struck a deal with Merck to license an ASO for Huntington disease—will be partnering with Eric, Sonia and the Broad Institute to develop an ASO that can lower prion protein in the brain as a drug for prion disease. As the World Congress meeting this week, Vallabh said that on the basis of preclinical results, which look promising thus far, they hope to begin clinical trials within five years.

They also published a study in the open access journal bioRxiv about a clinical study they launched last year at Massachusetts General Hospital to measure the level of prion protein in cerebrospinal fluid taken through a lumbar puncture. Initial findings from the ongoing study of nearly 50 volunteers—some with prion protein mutations and some without—is that prion protein can be detected in cerebrospinal fluid taken through a lumbar puncture, and that the levels of the protein remain stable over time.