Adeno-associated virus (AAV) vectors are pivotal in gene therapy for neurological disorders due to their ability to enable long-term gene expression in the central nervous system (CNS). However, transducing larger brains, such as those of non-human primates (NHPs), remains challenging, necessitating alternative delivery routes and optimized capsids. This study directly compares the transduction efficiency and biodistribution of the benchmark AAV9 and its engineered derivative, AAV-PHP.eB, following intracerebroventricular (i.c.v.) administration in juvenile Macaca nemestrina. Employing a neuron-specific promoter and nuclear-localized reporter, we systematically quantified transduction across cortical, subcortical, and spinal regions. AAV-PHP.eB demonstrated significantly higher transduction rates in cortical and spinal regions compared to AAV9, despite similar expression patterns. Both vectors exhibited limited subcortical penetration and significant peripheral leakage, highlighting key challenges in CNS targeting. This is the first study to quantitatively compare AAV-PHP.eB and AAV9 in NHPs, providing valuable insights into the advantages and limitations of engineered AAV capsids for CNS gene therapy. These findings lay a critical foundation for optimizing vector designs and delivery strategies to improve outcomes in clinical applications for neurodegenerative and neurodevelopmental disorders.
Scientific breakthroughs in the field of cell and gene therapy lay the groundwork for therapeutic innovation, but their translation and integration into routine care is delayed by systemic inefficiencies and limited cross-sector alignment. The Advanced Therapies model of Lund is a proactive and integrated approach designed to accelerate the development of advanced therapies from discovery to reimbursement, facilitating close collaboration among three main entities: university, hospital, and the iActors (a coalition of the innovation system, incubators, investors, and industry). Unlocking the full potential of therapeutic innovation requires inclusive and proactive engagement from all entities to accelerate development timelines, optimize resource use across the ecosystem, and ultimately deliver curative, cost-effective advanced therapies to patients. This will ensure broad patient access and establishment of optimal conditions for developing the next generation of cell and gene therapies, while also facilitating innovation and economic growth. To operationalize this model, we developed the Cell and Gene Therapy Navigator, a visualization instrument designed to track and optimize the development of advanced therapies within the model framework. This tool leverages three-dimensional visualization to provide a dynamic and comprehensive overview of progress of the advanced therapy development across the three crucial entities: university, hospital, and iActors. We are confident that working according to the model will minimize translational gaps and result in seamless good manufacturing practices (GMP) transfer, fewer re-works, faster time to first-in-human, and the creation of more viable biotech companies.
