The traditional target-based drug development strategy (in vitro screening) has had poor success in developing new drugs. The vast majority of Investigational New Drugs (INDs) fail in clinical trials due to toxicity or lack of efficacy. On the other hand, mammalian models are excellent tools to study disease mechanisms and test therapies but are difficult to use for large scale drug screening. Zebrafish have proven to be an ideal preclinical model due to the high number of genes shared with humans and the high percentage of genes associated with human disorders that have a zebrafish equivalent (see sidebar on Why Zebrafish).
With support from the Brain Canada platform grant, Xiao-Yan Wen and his multidisciplinary team from across Canada have built Z-BRAIN, a national high-throughput drug screening platform to target brain disorders, using zebrafish central nervous system (CNS) disease models for direct in vivo drug discovery on zebrafish embryos. Their team brings together specialists in drug development, robotic technologies, medicinal chemistry, bioinformatics, disease mechanisms and zebrafish modelling. The brain disorders targeted include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, ALS, epilepsy, schizophrenia, depression/stress, stroke and traumatic brain injury. Six industrial partners (Eli Lilly, Treventis Corporation, Atuka Inc., Edge Therapeutics Inc., Janssen Pharmaceutical, and Life Chemicals) and multiple international collaborators have joined this initiative.
Image of a retinal section viewed under the microscope showing retinal cells essential for vision labelled in different colours. Amacrine neurons are labelled in red and bipolar neurons are labelled in green. The blue staining marks all nuclei, highlighting the tri-layered structure of the neural retina with the light- sensing photoreceptor cells at the top of the image.
This CNS drug discovery platform is centered on existing CFI-funded drug screening infrastructure recently installed at St. Michael’s Hospital in Toronto, which allows robotic screening of zebrafish embryos carrying gene mutations or human transgenes. The platform is a state-of-the-art system that can perform fully automated screens from fish embryo sorting and drug dosing to efficacy readouts. The Brain Canada platform funding has greatly improved the platform’s performance. The funds have been used to hire new research staff to conduct computer and mechanical engineering work associated with the platform, as well as to hire staff for disease modelling, compound screening, drug database development and chemical informatics.
Since the beginning of the grant, the team has made significant progress in developing zebrafish disease models for Alzheimer’s disease, Parkinson’s disease, ALS, epilepsy, schizophrenia, vascular leakage/brain hemorrhage, fear/anxiety/stress and traumatic brain injury. Their research has also led to a Phase 2b clinical trial for one compound (Pimozide) identified from ALS zebrafish models. Several others are in the preclinical phase including screens for stroke and Alzheimer’s disease. They have also launched two spin-off companies, ZebraPeutics Inc. and DanioDesign Inc., for preclinical drug development and services in generating transgenic and mutant zebrafish lines.
Additionally, they have organized regular Z-BRAIN platform retreats and international zebrafish precision medicine conferences attracting over 200 researchers from Canada and around the world. These events bring together scientists from both biological and medical research fields to accelerate the translational process of zebrafish-based knowledge to clinical applications.
“No such platform currently exists anywhere in the world, and our novel initiative draws from Canadian as well as international expertise in neuroscience.”
— Xiao-Yan Wen, M.D., Ph.D. St. Michael’s Hospital