New Drugs to Prevent Schizophrenia Development and Progression
Using a protein-degrading system that crosses the blood-brain barrier to limit synaptic pruning and stop schizophrenia early
Technology Overview
Dr. James M. Olson
Schizophrenia affects 1 in 300 people worldwide. Although current treatments do not address its root causes, symptoms such as hallucinations and paranoia can be managed with psychotherapy and antipsychotic drugs. These drugs must be taken regularly and can have side effects including tremors, drowsiness and constipation. Many genetic, developmental and environmental factors influence the development of schizophrenia. Synaptic pruning — a normal nervous system process that removes unused or inefficient neuronal connections — might be a contributor to schizophrenia and a target for drug development through the complement system.
The complement system, which responds to infections by marking invading cells for destruction, also stimulates synaptic pruning at defined periods of development. Complement activity may contribute to schizophrenia progression by driving excessive synapse elimination. Individuals who are genetically predisposed to having high levels of complement component 4 (C4) have increased risk of developing schizophrenia after a psychotic episode. Drugs such as veculizumab and ravulizumab that inhibit the complement system can be prescribed for schizophrenia, but they act downstream of the point at which C4 promotes synaptic pruning.
Pediatric neuro-oncologist James M. Olson, MD, PhD, is collaborating with neuroscientist Nino Ramirez, PhD, and Invent postdoctoral scholar Akinsola Oyelakin, PhD, on a new protein therapeutic that directly addresses the link between high C4 levels and the risk of schizophrenia. The novel drugs, called BiCEPs (Bispecific Complement Engaging Proteins), are based on the CYpHER protein-degrading platform developed by research scientist Zachary Crook, PhD. BiCEPs are designed to cross the blood-brain barrier and reduce excess C4 in the central nervous system.
BiCEPs are composed of two domains: a small C4-binding antibody that is engineered to bind C4 in a pH-dependent fashion and a second domain that binds the transferrin receptor (TfR) on nearby cells. When a BiCEP molecule binds both C4 and TfR, TfR internalization causes the entire complex to be shuttled into an acidic endolysosome. In that low-pH environment, the C4 protein is released and degraded. The TfR, with the now-empty BiCEP, recycles to the cell surface to bind another C4 molecule for degradation.
This recycling mechanism allows a single BiCEP to eliminate multiple C4 molecules. By design, this strategy minimizes dosages when the C4-regulating drugs are available for clinical use. For obtaining preclinical evidence on drug candidates, the Olson Lab has access to transgenic animal models that overexpress human C4.
This project is supported by the Washington Research Foundation and accelerated by the Mark Torrance Foundation. The research team has extensive experience working with industry partners and Dr. Olson has cofounded multiple biotech companies. The researchers are interested in industry partnerships to advance the development, preclinical and clinical testing of BiCEPs as effective treatments that target a cause rather than the symptoms of schizophrenia.
Stage of Development
- Preclinical in vitro
- Preclinical in vivo
Partnering Opportunities
- Collaborative research and development
- Sponsored research agreement
- Consultation agreement
- Animal model access
- Licensing agreements
Publications
Crook ZR, Sevilla GP, Young P … Olson JM, et al. CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect. Nat Commun. 2024;15(1):8731.
Oyelakin A, Sosa J, Nayak KB, et al. An integrated genomic approach identifies follistatin as a target of the p63-epidermal growth factor receptor oncogenic network in head and neck squamous cell carcinoma. NAR Cancer. 2023;5(3):zcad038.
Glathar AR, Oyelakin A, Nayak KB, et al. A systemic and integrated analysis of p63-driven regulatory networks in mouse oral squamous cell carcinoma. Cancers. 2023;15(2):446.
Crook ZR, Girard EJ, Sevilla GP … Olson JM. Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager. Sci Transl Med. 2022;14(645):eabn0402.
Oyelakin A, Nayak KB, Glathar AR, et al. EHF is a novel regulator of cellular redox metabolism and predicts patient prognosis in HNSCC. NAR Canc. 2022;4(2):zcac017.
Crook ZR, Girard E, Sevilla GP … Olson JM. A TfR-binding cystine-dense peptide promotes blood-brain barrier penetration of bioactive molecules. J Mol Biol. 2020;432(14):3989-4009.
Crook ZR, Nairn NW, Olson JM. Miniproteins as a powerful modality in drug development. Trends Biochem Sci. 2020;45(4):332-346.
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