Origami Therapeutics CEO on harnessing autophagy to precisely target disease-causing proteins in the brain.
Aptly-named US biotech Origami Therapeutics is working to redefine how neurodegenerative diseases are treated, building on the biological insight that many disorders are driven by dysfunctional or “misfolded” proteins. By harnessing the body’s own natural protein disposal systems, the company aims to restore disease-causing proteins to their proper structure or eliminate them altogether.
With an initial focus on neurodegenerative diseases, including Huntington’s disease, Alzheimer’s, Parkinson’s, and other dementias, Origami recently announced a collaboration with biopharma giant Ipsen to develop a protein degrader program targeting an inherited neurodegenerative disorder. Such conditions are increasingly understood to share common underlying mechanisms, particularly disruptions in protein homeostasis and cellular waste clearance. By targeting these root causes, the company is seeking not only to slow the progression of neurodegeneration but to fundamentally alter its course.
Longevity.Technology: Origami’s broader ambition is to develop a pipeline of targeted protein degraders and protein conformation correctors that address the underlying biology of disease rather than its symptoms. The approach may ultimately have implications beyond neurodegeneration in other diseases linked to aging and systemic cellular decline. To learn more about why protein misfolding represents such a powerful unifying mechanism across many complex diseases, and how lessons from research in cystic fibrosis led to the formation of the company, we sat down with founder and CEO Dr Beth Hoffman.
A cell and molecular biologist by training, Hoffman has spent most of her career in neuroscience, spanning research at NIH through to directing drug development at Eli Lilly and Amgen. More recently, she led discovery at Vertex Pharmaceuticals, which is where the basis for Origami originated.
“At Vertex we worked on cystic fibrosis, and the essence of that work was using small molecules to fix a broken protein,” she explains. “Scientifically, the fascinating part was that very small molecules could change how proteins fold. Proteins are made like pearls on a string, but they must fold into the correct shape to function. If they don’t fold properly, they either lose function or gain a harmful function.”
Protein misfolding and disease
Protein misfolding is estimated to cause over 100 diseases and also occurs as part of aging. As the body ages, systems decline, including the ability of cells to maintain homeostasis.
“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 were able to address in cystic fibrosis and, by doing so, we transformed how the disease is treated and improved patients’ lives.”
After leaving Vertex, Hoffman wanted to return to neuroscience and felt there was an opportunity to apply what worked in cystic fibrosis to neurodegeneration.
“The basis is that cells are cells,” she says. “While lung epithelial cells and brain cells are specialized, the underlying principles are the same and the key is identifying commonalities. Many fundamental processes are universal across all living organisms – the differences are really just variations on those core principles.”
Having founded Origami in 2016, Hoffman initially set out to build a small molecule drug discovery platform that could tackle genetically defined neurodegenerative diseases.
“In these diseases, we know the cause – often a single mutated gene – so we know what to fix, who to recruit in clinical trials, and what to measure,” she says. “That may sound simple, but many drug failures happen because we don’t know the cause, don’t pick 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 leveraged advances in proteomics and genomics to conduct a “phenotypic screen.”
“Instead of targeting a specific gene, we asked the cell itself what works,” 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 identify effective molecules without assuming we knew the right target.”
The company’s platform leverages one of the most well-known cellular “garbage disposal” systems – the autophagy-lysosome pathway.
“In Huntington’s disease, the mutant protein actually disrupts this pathway,” says Hoffman. “Our small molecule changes the protein’s shape so it can be captured and degraded properly. By removing the mutant protein, we restore proteostasis, improving mitochondrial function, transcription, and clearing accumulated proteins.”
All of these effects are hot topics of discussion in aging and longevity circles, and Hoffman concurs, describing neurodegeneration as “premature aging.”
“If we can slow brain aging and keep the brain healthy, we extend healthspan – and that’s really what longevity is about,” she says.
Bringing precision to autophagy
While traditional small molecule inhibitors require strong binding to a specific active site, which limits their reach to a relatively small fraction of the proteome, Hoffman explains that Origami’s targeted protein degraders can act more flexibly, enabling the possibility of addressing the large proportion of proteins long considered “undruggable.”
“Many approaches try to simply activate autophagy, but it’s a double-edged sword – too much can stress cells,” says Hoffman. “Our approach is more precise. By asking the cell what works, we identify mechanisms that restore balance without causing toxicity.”
In addition to being focused on small molecules that can be administered orally and are capable of crossing the blood-brain barrier, Origami prioritizes compounds that demonstrate efficacy in human-derived disease models, with the goal of improving translation from preclinical studies into clinical outcomes.
“We focus on human disease models – primary cells, fibroblasts, and stem cell-derived neurons – because translation from animals to humans is often a challenge,” says Hoffman. “In these models, we’ve seen normalization of mitochondrial, nuclear, and protein degradation processes in a dose-dependent way. That gives us confidence.”
The path to the clinic
To date, Origami has been funded through Y Combinator, NuFund Venture Group, angels, high-net-worth individuals, non-dilutive grants, and SBIR funding.
“We’ll likely raise a small round soon and then a Series A later to expand into additional indications and build value,” says Hoffman. “The Ipsen partnership provides the resources and expertise to move into the clinic more rapidly. We’ll advance the research to a certain point, then Ipsen will take over for later-stage development.”
The company has now moved into early in vivo studies to ensure brain penetration of its compounds.
“In mouse models of Huntington’s disease, we reduce mutant protein while sparing the normal protein, which is critical,” says Hoffman. “Together, these results suggest our compounds have strong potential. The next step is safety studies before moving into the clinic. We’re about 18 months away from that.”
Crucially, Hoffman explains that studying genetic forms of neurodegeneration can help uncover insights into how broader forms of the diseases work – and that’s exactly what Origami has found.
“Some molecules will target specific proteins, while others may reveal broader pathways and targets,” she says. “We’ve identified multiple chemical scaffolds – one works on tau, which is involved in many neurodegenerative diseases. While not our lead program, it demonstrates that our approach can generalize. I expect we’ll even uncover targets applicable beyond neurodegeneration – potentially in areas like diabetes and other diseases.”
