CEO of Origami Therapeutics on using autophagy to precisely target disease-causing proteins in the brain.
Aptly named US Biotech Therapeutic origami is working to redefine the way neurodegenerative diseases are treated, relying on the biological understanding that many disorders are caused by dysfunctional or “wrong” proteins. Using the body’s natural protein systems, the company aims to restore diseased proteins to their proper structure or destroy them entirely.
With an initial focus on neurodegenerative diseases, including Huntington’s disease, Alzheimer’s, Parkinson’s and other dementias, Origami recently announced cooperation with the biopharma giant Ipsen development of a protein degradation program targeting inherited neurodegenerative disease. Such conditions are increasingly understood to share common underlying mechanisms, particularly disturbances in protein homeostasis and cellular waste clearance. By targeting these root causes, the company seeks to not only slow the progression of neurodegeneration, but to fundamentally change its course.
Continuity.Technology: Origami’s broader goal is to develop a pipeline of targeted protein degraders and protein conformation modifiers that address the underlying biology of disease rather than its symptoms. The relationship may ultimately have implications for neurodegeneration in other diseases associated with aging and systemic cell decline. To learn more about why protein errors represent a powerful unifying mechanism in many complex diseases and how lessons from research in cystic fibrosis have shaped the company, we sat down with founder and CEO Dr. Beth Hoffman.
A cell and molecular biologist by training, Hoffman has spent most of his career in neuroscience, spanning research at the NIH to leading drug development at Eli Lilly and Amgen. Most recently, he led the discovery at Vertex Pharmaceuticals, where Origami was founded.
“At Vertex, we worked on cystic fibrosis, and the essence of this work was to use small molecules to repair a broken protein,” he said. “Scientifically, the interesting part was that very small molecules can change the way proteins fold. Proteins are made like pearls on a string, but they have to be folded into the right shape. If they don’t fold correctly, they either lose function or develop a harmful function.”
Protein deficiency and disease
Protein misfolding is thought to cause more than 100 diseases and also occurs as part of aging. As the body ages, systems, including the ability of cells to maintain homeostasis, decline.
“Misfolded proteins are generally bad for cells—and what’s bad for cells is bad for organs and the body,” says Hoffman. “That’s what we’ve been able to do in cystic fibrosis, and in doing so, we’ve changed the way we treat this disease and improved the lives of patients.”
After leaving Vertex, Hoffman wanted to return to neuroscience and felt there was an opportunity to apply what was working in cystic fibrosis to neurodegeneration.
“The bottom line is that cells are cells,” he says. “While lung epithelial cells and brain cells are specialized, the underlying principles are the same, and the key is to identify commonalities. Many fundamental processes are universal across all living organisms—the differences are really just variations on these basic principles.”
After founding Origami in 2016, Hoffman initially built a small-molecule drug discovery platform that could fight genetically determined neurodegenerative diseases.
“In these diseases, we know the cause—often a mutated gene—so we know what to fix, who to put in clinical trials, and what to measure,” he says. “It may sound simple, but many drug failures occur because we don’t know the cause, don’t choose the right target, or don’t measure the right outcomes. Even if a drug is safe, if you can’t show it works in the right patients, it won’t succeed.”
Phenotypic screening
To find potential molecules capable of targeting specific proteins, Origami used advances in proteomics and genomics to conduct a “phenotypic screen.”
“Instead of targeting a specific gene, we asked the cell itself what it was doing,” says Hoffman. “We screened compounds based on their ability to reduce the mutant protein. This approach helped us understand the mechanism and allowed us to find effective molecules without assuming we knew the correct target.”
The company’s platform uses one of the most famous cellular “garbage” systems – the autophagy-lysosome pathway.
“In Huntington’s disease, the mutant protein actually disrupts this pathway,” Hoffman says. “Our small molecule changes the shape of the protein so that it can be taken up and degraded properly. By removing the mutant protein, we restore proteostasis, improving mitochondrial function, transcription, and clearance of aggregated proteins.”
All of these effects are hot topics of debate in aging and longevity circles, and Hoffman agrees, describing neurodegeneration as “premature aging.”
“If we can slow down brain aging and keep the brain healthy, we can extend healthy life spans — and that’s really longevity,” he says.
It precisely leads to autophagy
While traditional small molecule inhibitors require strong binding to a specific active site, which limits their access to a relatively small fraction of the proteome, Hoffman explains that Origami’s targeted protein degraders can act more flexibly, providing the opportunity to address a large proportion of proteins that have long been considered “unstable.”
“Many approaches try to activate autophagy, but this is a double-edged sword – too much can stress the cells,” says Hoffman. “Our approach is more precise. By asking the cell what it is doing, we identify mechanisms that restore balance without toxicity.”
In addition to focusing on small molecules that can be administered orally and are able to cross the blood-brain barrier, Origami prioritizes compounds that demonstrate efficacy in human disease models, with the goal of improving translation from preclinical studies to clinical outcomes.
“We focus on human disease models—primary cells, fibroblasts, and neuronal stem cells—because translation from animals to humans is often difficult,” says Hoffman. “In these models, we had growth-dependent normalization of mitochondrial, nuclear, and protein degradation processes. This gives us confidence.”
Road to the clinic
To date, Origami has been funded through Y Combinator, NuFund Venture Group, angels, high net worth individuals, non-profit grants, and SBIR funding.
“We’ll likely raise a small round soon and then a Series A to expand and add value to additional indications,” Hoffman says. “The Ipsen partnership will provide the resources and expertise to get to the clinic faster. We will advance the research to a certain point, and then Ipsen will take over for later-stage development.”
The company has now moved to early alive researches are conducted to ensure the penetration of its compounds into the brain.
“In mouse models of Huntington’s disease, we reduce the mutant protein while sparing the normal protein, which is important,” says Hoffman. “Together, these results show that our compounds have strong potential. The next step is a safety study before moving to the clinic. We’re about 18 months away from that.”
More importantly, Hoffman explains, studying the genetic patterns of neurodegeneration can help reveal insights into how broader patterns of disease work—and that’s exactly what Origami found.
“Some molecules target specific proteins, while others may reveal broader pathways and targets,” he says. “We’ve identified a number of chemical pathways—one working in tava—that’s involved in many neurodegenerative diseases. Although not our leading application, it shows that our approach can be generalized. Hopefully, we’ll even discover targets applicable beyond neurodegeneration—potentially in the areas of diabetes and other diseases.”
