Our Science
What is protein degradation?
The control of protein levels is accomplished with a small molecule drug called a degrader. Degraders takes advantage of natural cellular processes where the overall outcome is the destruction of the protein by natural degradation pathways such as the proteasome and the lysosome.
Degraders are different than inhibitors
An inhibitor typically blocks the activity of a target protein temporarily. A degrader is able to eliminate disease-causing proteins through proteasome or lysosome degradation of the target protein. A degrader can target proteins that do not have identified binding sites and therefore, can target proteins typically considered undruggable.
Our Technology
Origami is a pioneer of targeted protein degradation technology – our founder was instrumental in the discovery of the first FDA-approved protein conformation correctors for Cystic Fibrosis. Our platform enables discovery of both protein degraders and protein conformation correctors, allowing us to match the best drug to treat each disease using patient-derived disease models.
Targeted protein degradation is one of the most promising areas of medical research and we are establishing a new scientific frontier by challenging the perceived limits of drug discovery.
We are engineering an expansive pipeline of disease-modifying therapeutics for neurodegenerative diseases. Our ORIGAMI protein degraders are designed to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins while sparing normal forms of the protein.
Origami’s mediated protein degradation platform has multiple benefits over other modalities:
Targeting the “Undruggable” – Traditional small molecule inhibitors require strong binding to a target protein, often to its active site. Since ORIGAMI protein degraders only need to bind weakly to the target protein in order to specifically “tag” it, the ~80% of the proteome that is currently “undruggable” may be addressable by our degraders and correctors.
Oral routes of administration – We will develop ORIGAMI protein degraders and correctors to be delivered orally, and additional routes of administration will be considered depending on the disease and the need.
Crossing the blood/brain barrier – ORIGAMI protein degraders and correctors will be selected based on their ability to penetrate the blood-brain barrier, a key step in developing drugs to treat neurodegenerative diseases.
Potential to prevent spread of disease-causing proteins – ORIGAMI protein degraders and correctors enter cells and prevent the spread of pathogenic proteins to other neighboring cells.
Benefits of small molecules – In contrast to some other novel modalities, ORIGAMI protein degraders have broad distribution in the body and can be easily manufactured compared to biologics.
Our Discovery Platform
Treating Disease in a New Way: Targeted Protein Degradation and Correction
Origami Therapeutics is working at the forefront of new and exciting unique modalities called targeted protein degradation (TPD) and targeted protein conformation correction to invent new medicines for diseases with limited or no known treatment options, that are capable of targeting proteins traditionally undrugged by small molecules.
The key components of our drug discovery platform combine Origami’s broad understanding of the localization and expression levels of the hundreds of proteins in the human body with our proprietary drug discovery platform, as well as our chemistry, biology, and computational capabilities to develop protein degraders that address significant, unmet medical needs in neurodegenerative diseases.
With the flexibility to design protein degraders and stablizers, we can address different neurodegenerative disease-causing proteins with a targeted approach.
Neurodegenerative disorders caused by protein misfolding include:
- Alzheimer’s disease (APP, ApoE4)
- ALS (SOD, TDP43, C9orf72)
- Parkinson’s disease (alpha-SYN)
- Huntington’s disease (HTT)
Modeling Neurological Diseases with Human Brain Organoids
Currently available animal models that are used in the pre-clinical phase to test new interventions are imperfect and are not a good mimic of human disease, leading to a high failure rate for drug development.
The use of human cells in two-dimensional cultures as disease models has gained greater attention in therapeutic discovery. For neurological disorders, these systems generally do not model the more prevalent adult-onset diseases. Thus, there is a need for better human disease model systems.
Brain organoids derived from human pluripotent stem cells (PSCs) provide a new tool to model both normal and pathological human brain in three-dimensions, and greatly enhance our ability to study brain biology and diseases. Currently, human brain organoids are increasingly used in modeling neurological disorders with the hope that they will be readily applicable to therapeutic discovery. Due to limitations in organoid culturing for drug discovery, Origami is pioneering the adoption of spheroids, a somewhat simpler 3D system, due to its greater reproducibility which is critical for drug discovery. This review article focuses on recent advances in human brain organoid systems and their application in disease modeling. It also discusses the limitations and future perspective of human brain organoids in modeling neurological diseases.
About mHTT
The mutant HTT (mHTT) protein retains normal function. Under conditions of reduced proteostasis where cell machinery is less able to keep protein properly folded, mHTT tends to unfold and misfold, leaving it susceptible to cleavage by cellular proteases with the release of toxic mHTT protein fragments. These toxic protein fragments exert a toxic gain-of-function in transcriptional regulation and axonal transport by sequestrating other proteins aberrantly. The fragments result in a broad array of cell dysfunctions, pathologies including protein aggregates and ultimately cell death. In HD, the generation of toxic fragments from misfolded mHTT is considered a main cause of pathogenesis, thus it would be rational to prevent the misfolding of mHTTproteins or to direct such misfolded forms to degradation pathways to cure the disease. Origami’s compounds limit formation of toxic mHTT protein fragments. Targeting mHTT corrects the underlying cause of the disease – which is mHTT protein misfolding.
Proprietary Chemistry
Our expertise in uncovering the molecular principles responsible for the properties of this new class of small molecules provides us the opportunity to design degraders with optimized pharmaceutical properties tailored to not only specific diseases but to selected subsets of patient populations within a specific disease.
Origami Therapeutics is taking a precision medicine approach to discover disease-modifying treatments for genetic neurodegenerative disorders caused by toxic protein misfolding.
Leveraging the Founder’s experience in discovering transformational therapies for Cystic Fibrosis that modulate CFTR conformation, the Company’s focus is to treat neurodegeneration by directly modulating the pathogenic proteins that cause disease in order to restore physiologic balance.
Our discovery platform enables discovery of both protein degraders and conformation correctors, allowing us to match the best drug to treat each disease by using patient-derived disease models to ensure success in clinical trials.