Alzheimer’s disease (AD) is a neurodegenerative disease that causes a reduction in brain-derived neurotrophic factor (BDNF) in multiple animal models, and delivery of BDNF provides neuroprotective effects in those disease models. BDNF regulates a wide range of biological functions in the human body, and therapeutic delivery requires effective delivery routes and targeting specificity.

Adeno-associated viral (AAV) vector systems have recently become popularized for targeted gene delivery. AAVs are non-pathogenic in humans, provide long-term gene expression,

and do not integrate into the host genome. Despite the advancements in viral gene therapy over the past decades, AAV vector systems are limited by the lack of regulation.

Here, we developed a novel regulatable dual AAV vector system for therapeutic delivery of BDNF that can be turned off by oral administration of tamoxifen to adult mice. Our dual AAV vector system contains two co-dependent AAV vectors. One vector carries a pancellular promoter and the BDNF transgene. The second vector carries a drug-inducible Cre recombinase enzyme (Cre) that we hypothesize will result in degradation of the AAV genome and elimination of gene expression.

We found that our dual vector system provides a modest reduction in AAV gene expression following administration of tamoxifen. Further optimization of the system could lead to the first regulatable AAV system suitable for clinical applications. This regulation could act as an “off” switch for eliminating gene expression in the event of adverse side-effects. Moreover, this regulation could allow for transient gene delivery for treating medical conditions such as traumatic brain injury and spinal cord injury. The ability to tightly regulate AAV gene expression is potentially applicable to all 105 on-going clinical trials involving AAV gene therapy.