QSP model for AAV-mediated antibody delivery in rat brain

Area of Science:

• Pharmacology
• Biotechnology
• Neuroscience

Background:

• Adeno-associated virus (AAV) mediated monoclonal antibody (mAb) expression is a potential therapy for CNS disorders.
• Systemic mAb administration faces challenges in treating CNS diseases.
• AAV offers a one-and-done therapeutic approach for brain disorders.

Purpose of the Study:

• To develop an AAV-transgene-target quantitative systems pharmacology (QSP) model.
• To characterize the disposition of AAV, expressed antibody, target, and mAb-target complex.
• To guide the development of AAV therapies for neurological disorders.

Main Methods:

• Integrated previously published physiologically based pharmacokinetic (PBPK) models for AAV, protein therapeutics, and brain.
• Focused on transport pathways and transduction mechanisms within the brain.
• Captured pharmacokinetics of AAV and expressed mAb in systemic circulation and brain tissues in rats.

Main Results:

• The QSP model accurately predicted AAV and mAb pharmacokinetics following various administration routes.
• Intra-cisternal magna or intrastriatal AAV injection showed better therapeutic potential than intravenous administration.
• Local AAV administration predicted sufficient antibody exposure and target engagement with minimal systemic exposure.

Conclusions:

• The developed QSP model supports cross-species and cross-serotype translation of AAV PBPK models.
• QSP modeling is a valuable tool for guiding AAV therapy development for neurological disorders.
• Local AAV delivery strategies optimize efficacy and minimize toxicity for CNS treatments.