DoD Discovery Award to Develop Human Vascular Malformation Model From iPSCs
BioE Associate Professor Guohao Dai received a $314K Discovery Award from the Department of Defense for “Human iPSCs derived 3D perfused model of vascular malformation”.
Vascular malformations (VMs) refer to the malformed blood vessels. They are heterogeneous groups of diseases affecting a large population. VMs are caused by genetic mutations in genes involved in blood vessel development. VMs have a major impact on the quality of life of patients; they are painful and disfiguring and may lead to bleeding, recurrent infections, thrombosis, organ dysfunction, and even death. Current therapies for VMs are very limited, the only options are laser treatment and surgery. However, these treatments are insufficient, and patients often experience a high risk of recurrence and progression. In addition, surgical treatment cannot be applied to tissues that are critical for normal function such as certain areas of the brain. Therefore, there is a critical need to develop a pharmacological treatment for VMs. However, doing so requires the development of in vivo or in vitro models of VMs that recreate the disease pathology of human VMs.
To overcome these challenges, this project will develop human iPSCs-based model of VMs. Dr. Dai’s lab will use their expertise in 3D bioprinting, vascular biology, and stem cells to create 3D perfused vasculature from iPSCs, and then establish two models of VMs by introducing specific genetic mutations using CRISPR gene editing, and demonstrate its ability for investigating disease biology. They will then validate the models by assessing candidate therapies and compare to existing clinical trials. Completion of this project will lead to novel human cell-based VM models. Developing such models will have great significance: (1) study the pathogenesis of disease using human cells; (2) lower the cost of developing new drugs for VMs; (3) screening the candidate drugs for patient-specific therapy while lower the side effects. In the future, other types of VMs caused by various mutations can be easily established and studied using the same platform. This will allow personalized medicine to quickly test candidate therapies for specific patients, thereby benefiting a large population.
Due to the heterogeneous nature of the diseases which are caused by different mutations and thus different pathophysiology, the market size for a specific drug is very small. Thus, there is very little incentive from pharmaceutical companies to invest in the development of new drugs for each subtype of VMs due to lack of profitability. As a result of this, a lot of patients are left out without proper treatment. With DoD’s support, the proposed project will have a direct impact to benefit the military service members, veterans, and families who are suffering from VMs. “We are grateful that DoD is willing to invest in this disease, which is not profitable for big pharma,” Dai said, “this project will not only benefit military families who suffer from the diseases, but also beneficial to a larger general population.”