Tianwen LI, PhD, MD | Huashan Hospital, Fudan Universiy; Jianhong ZHU, PhD, MD; Qisheng TANG, PhD; Tongming ZHU, PhD, MD; Peng WANG, PhD, MD; Fengshi LI, PhD, MD; Jingyu YU, PhD, MD;Xiao FAN, PhD, MD; Chen CHENG, PhD, MD
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2024
As individuals age, the blood-brain barrier (BBB) undergoes structural and functional deterioration, including loosening of endothelial cell junctions, reduced transporter function, increased inflammation, and oxidative stress. BBB disruption allows harmful substances and immune cells from the blood to infiltrate the brain, triggering inflammation and damaging neurons and oligodendrocytes. Moreover, BBB disruption is implicated in various neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD), where it accelerates the accumulation of harmful proteins like β-amyloid and α-synuclein, exacerbating disease progression. Effective BBB repair could significantly delay aging and provide novel therapeutic strategies for neurodegenerative diseases.
Neural stem cells (NSCs), known for their self-renewal and differentiation potential, mediate neurorepair through immune modulation and local proliferation. However, their direct protective role in BBB repair remains unclear. In this study, we identified CD40 as a key molecule involved in BBB disruption related to aging and AD. Using synthetic biology, we engineered Anti-CD40::SynNotch NSCs, which exhibit a natural tropism for BBB disruption and incorporate a reporter protein strategy to monitor age-related BBB breakdown. Furthermore, we modified the BBB repair protein Wnt7a (Wnt7a-K190A) for enhanced safety and efficacy. Upon recognition of CD40, engineered NSCs produce and secrete Wnt7a-K190A, activating BBB repair pathways through Gpr124 receptor binding on endothelial cells.
This approach, utilizing SynNotch technology and nasal administration, combines precision, safety, and therapeutic potential for treating AD, PD, and delaying brain aging by stabilizing the BBB and maintaining homeostasis.