Results
The blood brain project over time
The BBB Project set out to overcome the significant challenge of delivering therapeutic agents across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), a critical hurdle in treating central nervous system (CNS) disorders like Alzheimer’s disease.
The project's initial goals were to identify VHHs (nanobodies) capable of crossing these barriers through an unbiased approach, validate an in vivo non-human primate (NHP) screening platform, and demonstrate efficacy in a model of breast cancer brain metastasis.
As the project progressed, significant proof-of-principle was achieved for the core research hypothesis: the feasibility of in vivo screening for BBB/BCSFB-crossing VHHs. Several promising nanobodies were discovered, validated, and shown to successfully cross these barriers. Additionally, a novel brain sampling probe was developed and validated, enabling longitudinal sampling in vivo, a critical advancement for studying drug delivery over extended periods.
Early challenges led to a strategic adjustement involving the generation of more focused libraries by targeting approximately 50 BBB-related proteins identified through data mining. This resulted in the successful creation of targeted libraries and identification of VHHs with crossing potential. Further, the project achieved successful long-term peripheral expression of nanobodies in NHPs and secured a patent for the innovative brain sampling probe.
While some collaborations faced setbacks due to the COVID-19 pandemic and technical limitations, new partnerships and methodologies were explored. These efforts yielded important discoveries, including anti-TfR nanobodies capable of delivering therapeutic payloads across the BBB, which have attracted significant interest from pharmaceutical companies and resulted in scientific publications and patent applications. Additionally, breakthroughs were made in validating nanobodies targeting CD98hc, basigin, and the insulin receptor, as well as BCSFB-crossing nanobodies against FOLR1, leading to a patent filing and further research developments.
The BBB project has made substantial progress in developing strategies for overcoming the BBB/BCSFB, advancing our ability to target the brain with therapeutic agents. These innovations hold great potential for improving treatments for Alzheimer’s disease and other CNS disorders, with the prospect of significant clinical and commercial impact.